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  • 1.
    Brown, Russell D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Turner, Anita J.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Gibson, Karen J.
    Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney2011In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 300, no 6, p. F1368-F1374Article in journal (Refereed)
    Abstract [en]

    Brown RD, Turner AJ, Carlstrom M, Persson AE, Gibson KJ. Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney. Am J Physiol Renal Physiol 300: F1368-F1374, 2011. First published March 30, 2011; doi:10.1152/ajprenal. 00019.2011.-The tubuloglomerular feedback mechanism (TGF) plays an important role in regulating single-nephron glomerular filtration rate (GFR) by coupling distal tubular flow to arteriolar tone. It is not known whether TGF is active in the developing kidney or whether it can regulate renal vascular tone and thus GFR during intrauterine life. TGF characteristics were examined in late-gestation ovine fetuses and lambs under normovolemic and volume-expanded (VE) conditions. Lambs and pregnant ewes were anesthetized and the fetuses were delivered via a caesarean incision into a heated water bath, with the umbilical cord intact. Under normovolemic conditions, mean arterial pressure of the fetuses was lower than lambs (51 +/- 1 vs. 64 +/- 3 mmHg). The maximum TGF response (Delta P(SFmax)) was found to be lower in fetuses than lambs when tubular perfusion was increased from 0 to 40 nl/min (5.4 +/- 0.7 vs. 10.6 +/- 0.4 mmHg). Furthermore, the flow rate eliciting half-maximal response [turning point (TP)] was 15.7 +/- 0.9 nl/min in fetuses compared with 19.3 +/- 1.0 nl/min in lambs, indicating a greater TGF sensitivity of the prenatal kidney. VE decreased Delta P(SFmax) (4.2 +/- 0.4 mmHg) and increased TP to 23.7 +/- 1.3 nl/min in lambs. In fetuses, VE increased stop-flow pressure from 26.6 +/- 1.5 to 30.3 +/- 0.8 mmHg, and reset TGF sensitivity so that TP increased to 21.3 +/- 0.7 nl/min, but it had no effect on Delta P(SFmax). This study provides direct evidence that the TGF mechanism is active during fetal life and responds to physiological stimuli. Moreover, reductions in TGF sensitivity may contribute to the increase in GFR at birth.

  • 2.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Brown, Russell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Edlund, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Teerlink, Tom
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wåhlin, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals2008In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 294, no 2, p. 362-370Article in journal (Refereed)
    Abstract [en]

    Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N-G- nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.

  • 3. Ding, Mei
    et al.
    Coward, Richard J
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Kim, William
    Quaggin, Susan E
    Regulation of hypoxia-inducible factor 2-a is essential for integrity of the glomerular barrier2013In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 304, no 1, p. F120-F126Article in journal (Refereed)
    Abstract [en]

    Deletion of the von Hippel-Lindau tumor suppressor (Vhl) gene from renal podocytes of mice (podVhl KO) leads to rapidly progressive glomerulonephritis (RPGN), a clinical syndrome characterized by rapid loss of renal function and crescents on renal biopsy. Genomic profiling of glomeruli isolated from podVhl knockout (KO) mice and from patients with RPGN identified a fingerprint of genes regulated by hypoxia-inducible factors (HIF), important substrates of the product of the VHL gene. Here, we show that stabilization of Hifs in podocytes is both required and sufficient for the glomerular phenotype observed in podVhl KO mice. Genetic deletion of the obligate dimerization partner Arnt/Hif1b that is essential for Hif transcriptional function rescues the phenotype. Conversely, stabilization of HIF2A alone in podocytes results in crescentic glomerular disease. Together, our results show that the Hif pathway and Hif2a in particular are key players in maintenance of the glomerular barrier.

  • 4.
    Franzén, Stephanie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Pihl, Liselotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats2018In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 3, p. F439-F444Article in journal (Refereed)
    Abstract [en]

    About one-third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease, including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (sarafotoxin 6c for 30-40 min; 0.78 pmol/h directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague-Dawley rats administered streptozotocin (55 mg/kg) 2 wk before the acute experiments. Intrarenal activation of ETB-R improved oxygenation in the hypoxic diabetic kidney. However, the effects on diabetes-induced increased kidney oxygen consumption could not explain the improved oxygenation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery without increasing glomerular filtration or tubular sodium load. In conclusion, increased ETB-R signaling in the diabetic kidney improves intrarenal tissue oxygenation due to increased oxygen delivery secondary to increased renal blood flow.

  • 5. Helle, Frank
    et al.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Skogstrand, Trude
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Iversen, Bjarne
    Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C2009In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 296, no 1, p. F78-F86Article in journal (Refereed)
    Abstract [en]

    Two-kidney, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca(i)(2+)) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140-F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10(-7) mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME). In AAs from the nonclipped kidney, l-NAME increased the ANG II-induced Ca(i)(2+) response from 0.28 +/- 0.05 to 0.55 +/- 0.09 (fura 2, 340 nm/380 nm ratio) and increased contraction from 80 +/- 6 to 60 +/- 6% of baseline (P < 0.05). In vessels from sham and clipped kidneys, l-NAME had no effect. In diaminofluorescein-FM diacetate-loaded AAs from the nonclipped kidney, ANG II increased NO-derived fluorescence to 145 +/- 34% of baseline (P < 0.05 vs. sham), but not in vessels from the sham or clipped kidney. Endothelial NOS (eNOS) mRNA and ser-1177 phosphorylation were unchanged in both kidneys from 2K1C, while eNOS protein was reduced in the clipped kidney compared with sham. Cationic amino acid transferase-1 and 2 mRNAs were increased in 2K1C, indicating increased availability of l-arginine for NO synthesis, but counteracted by decreased scavenging of the eNOS inhibitor asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolase 2. In conclusion, the Ca(i)(2+) and contractile responses to ANG II are blunted by NO release in the nonclipped kidney. This may protect the nonclipped kidney from the hypertension and elevated ANG II levels in 2K1C.

  • 6. Helle, Frank
    et al.
    Skogstrand, Trude
    Schwartz, Idit F
    Schwartz, Doron
    Iversen, Bjarne Magnus
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine2013In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 304, no 8, p. F1088-F1098Article in journal (Refereed)
    Abstract [en]

    Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of L-arginine. The experiments were performed in rats two days (early) or six weeks (late) after UNX and compared to controls (Sham) to study acute and chronic effects on NO metabolism. Renal blood flow was increased after UNX (21±2 ml/(min*kg) in sham, 30±3 in early, and 26±1 in late, P<0.05). NO inhibition with L-NAME caused a greater increase in renal vascular resistance in early UNX compared to Sham and late UNX (138±24% vs. 88±10% and 84±7%, P<0.01). The lower limit of autoregulation was increased both in early and late UNX compared to Sham (P<0.05). L-NAME did not affect the Ang II induced contraction of isolated afferent arterioles (AA) from Sham. AA from early UNX displayed a more pronounced contraction in response to L-NAME (-57±7% vs. -16±7%, P<0.05), and in the absence of L-arginine (-41±4%, P<0.05) compared to both late UNX and Sham. mRNA expression of endothelial NO synthase was reduced, whereas protein expression was unchanged. Cationic amino acid transporters-1 and -2 mRNA were increased, while protein was unaffected in isolated preglomerular resistance vessels. In conclusion, NO-dependent hyperperfusion of the remaining kidney in early UNX is associated with increased NO-release from the afferent arteriole which is highly dependent on extracellular L-arginine availability.

  • 7. Hultström, Michael
    et al.
    Helle, Frank
    Iversen, Bjarne M
    AT(1) receptor activation regulates the mRNA expression of CAT1, CAT2, arginase-1, and DDAH2 in preglomerular vessels from angiotensin II hypertensive rats.2009In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 297, no 1, p. F163-8Article in journal (Refereed)
    Abstract [en]

    Previously, we found increased expression of l-arginine metabolizing enzymes in both kidneys from two-kidney, one-clip (2K1C) hypertensive rats (Helle F, Hultstrom M, Skogstrand T, Palm F, Iversen BM. Am J Physiol Renal Physiol 296: F78-F86, 2009). In the present study, we investigate whether AT(1) receptor activation can induce the changes observed in 2K1C. Four groups of rats were infused with 80 ng/min ANG II or saline for 14 days and/or given 60 mg x kg(-1) x day(-1) losartan. Gene expression was studied in isolated preglomerular vessels by RT-PCR. Dose-responses to ANG II were studied in isolated preglomerular vessels with and without acute NOS inhibition [10(-4) mol/l N(G)-nitro-l-arginine methyl ester (l-NAME)]. Expressions of endothelial nitric oxide synthase (eNOS), caveolin-1, and arginase-2 were not changed by ANG II infusion. CAT1 (0.3 8 +/- 0.07 to 0.73 +/- 0.12, P < 0.05), CAT2 (1.14 +/- 0.29 to 2.74 +/- 0.48), DDAH2 (1.09 +/- 0.27 to 2.3 +/- 0.46), and arginase-1 (1.08 +/- 0.17 to 1.82 +/- 0.22) were increased in ANG II-infused rats. This was prevented by losartan treatment, which reduced the expression of eNOS (0.97 +/- 0.26 to 0.37 +/- 0.11 in controls; 0.8 +/- 0.16 to 0.36 +/- 0.1 in ANG II-infused rats) and caveolin-1 (2.49 +/- 0.59 to 0.82 +/- 0.24 in controls and 2.59 +/- 0.61 to 1.1 +/- 0.25 in ANG II-infused rats). ANG II (10(-10) mol/l) caused vessels from ANG II-infused animals to contract to 53 +/- 15% of baseline diameter and 90 +/- 5% of baseline diameter in controls (P < 0.05) and was further enhanced by l-NAME to 4 +/- 4% of baseline diameter (P < 0.05). In vivo losartan treatment reduced the reactivity of isolated vessels to 91 +/- 2% of baseline in response to 10(-7) mol/l ANG II compared with 82 +/- 3% in controls (P < 0.05) and prevented the increased responsiveness caused by ANG II infusion. In conclusion, CAT1, CAT2, DDAH2, and arginase-1 expression in renal resistance vessels is regulated through the AT(1) receptor. This finding may be of direct importance for NOS and the regulation of preglomerular vascular function.

  • 8.
    Jeansson, Marie
    et al.
    Göteborgs Universitet.
    Haraldsson, Börje
    Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier2006In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, American journal of physiology., Vol. 290, no 1, p. F111-F116Article in journal (Refereed)
    Abstract [en]

    In this study, we pursued the somewhat controversial issue whether the glycosaminoglycans (GAG) in the endothelial cell glycocalyx are important for glomerular size and charge selectivity. In isoflurane-anesthetized mice, Intralipid droplets were used as indirect markers of the glomerular endothelial cell-surface layer, i.e., the glycocalyx. The mice were given intravenous injections of GAG-degrading enzymes, which due to their high molecular weight remained and acted intravascularly. Flow-arrested kidneys were fixed and prepared for electron microscopy, and the distance between glomerular endothelial cells and the luminal Intralipid droplets was measured. The relative frequency of Intralipid droplets was calculated for each 50-nm increment zone up to 500 nm from the endothelial cell membrane surface as were the mean distances. Glomerular size and charge selectivity were estimated from the clearance data for neutral Ficolls (molecular radii of 12-72 A), and albumin in isolated kidneys was perfused at 8 degrees C. In enzyme-treated animals (hyaluronidase, heparinase, and chondroitinase), the relative Intralipid droplet frequency in the zone closest to the endothelial cells, i.e., 0-50 nm, was increased approximately 2.5 times compared with controls. Also, the mean distance between the Intralipid droplets and the endothelium was decreased from 176 to 115-122 nm by enzyme treatment. These changes were accompanied by an increase in the fractional clearance for albumin. In conclusion, both morphological and functional measurements suggest the endothelial cell glycocalyx to be an important component of the glomerular barrier.

  • 9. Lai, En Yin
    et al.
    Luo, Zaiming
    Onozato, Maristela L
    Rudolph, Earl H
    Solis, Glenn
    Jose, Pedro A
    Wellstein, Anton
    Aslam, Shakil
    Quinn, Mark T
    Griendling, Kathy
    Le, Thu
    Li, Ping
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welch, William J
    Wilcox, Christopher S
    Effects of the antioxidant drug tempol on renal oxygenation in mice with reduced renal mass.2012In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 303, no 1, p. F64-74Article in journal (Refereed)
    Abstract [en]

    We tested the hypothesis that reactive oxygen species (ROS) contributed to renal hypoxia in C57BL/6 mice with &frac56; surgical reduction of renal mass (RRM). ROS can activate the mitochondrial uncoupling protein 2 (UCP-2) and increase O(2) usage. However, UCP-2 can be inactivated by glutathionylation. Mice were fed normal (NS)- or high-salt (HS) diets, and HS mice received the antioxidant drug tempol or vehicle for 3 mo. Since salt intake did not affect the tubular Na(+) transport per O(2) consumed (T(Na/)Q(O2)), further studies were confined to HS mice. RRM mice had increased excretion of 8-isoprostane F(2α) and H(2)O(2), renal expression of UCP-2 and renal O(2) extraction, and reduced T(Na/)Q(O2) (sham: 20 ± 2 vs. RRM: 10 ± 1 μmol/μmol; P < 0.05) and cortical Po(2) (sham: 43 ± 2, RRM: 29 ± 2 mmHg; P < 0.02). Tempol normalized all these parameters while further increasing compensatory renal growth and glomerular volume. RRM mice had preserved blood pressure, glomeruli, and patchy tubulointerstitial fibrosis. The patterns of protein expression in the renal cortex suggested that RRM kidneys had increased ROS from upregulated p22(phox), NOX-2, and -4 and that ROS-dependent increases in UCP-2 led to hypoxia that activated transforming growth factor-β whereas erythroid-related factor 2 (Nrf-2), glutathione peroxidase-1, and glutathione-S-transferase mu-1 were upregulated independently of ROS. We conclude that RRM activated distinct processes: a ROS-dependent activation of UCP-2 leading to inefficient renal O(2) usage and cortical hypoxia that was offset by Nrf-2-dependent glutathionylation. Thus hypoxia in RRM may be the outcome of NADPH oxidase-initiated ROS generation, leading to mitochondrial uncoupling counteracted by defense pathways coordinated by Nrf-2.

  • 10. Laustsen, Christoffer
    et al.
    Nielsen, Per Mose
    Nørlinger, Thomas Stokholm
    Qi, Haiyun
    Pedersen, Uffe Kjærgaard
    Bertelsen, Lotte Bonde
    Østergaard, Jakob Appel
    Flyvbjerg, Allan
    Ardenkjær-Larsen, Jan Henrik
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Stødkilde-Jørgensen, Hans
    Antioxidant treatment attenuates lactate production in diabetic nephropathy2017In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 312, no 1, p. F192-F199Article in journal (Refereed)
    Abstract [en]

    The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-(13)C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned (13)C/(1)H-volume rat coil. The rats received intravenous hyperpolarized [1-(13)C]pyruvate and were imaged using a slice-selective (13)C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [(13)C]alanine levels, indicating an intact glucose-alanine cycle, or [(13)C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.

  • 11.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Brown, Russell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption2009In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 297, no 5, p. F1265-F1272Article in journal (Refereed)
    Abstract [en]

    C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (T(Na)) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (QO2), T(Na), fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent QO2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (-24%), stop-flow pressure (-8%), and filtration fraction (-17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline T(Na) (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline QO2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.

  • 12. O'Neill, Julie
    et al.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pihl, Liselotte
    Patinha, Daniela
    Franzen, Stephanie
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Acute SGLT inhibition normalizes O-2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats2015In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 309, no 3, p. F227-F234Article in journal (Refereed)
    Abstract [en]

    Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue PO2. Recent observations have indicated that increased tubular Na+-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon PO2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O-2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline PO2 in both the cortex and medulla. SGLT inhibition improved cortical PO2 in the diabetic kidney, whereas it reduced medullary PO2 in both groups. SGLT inhibition reduced Na+ transport efficiency [tubular Na+ transport (TNa)/renal O-2 consumption (QO(2))] in the control kidney, whereas the already reduced TNa/QO(2) in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex PO2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary PO2 in both control and diabetic kidneys during the inhibition of proximal Na+ reabsorption suggests the redistribution of active Na+ transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

  • 13.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney2010In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 298, no 2, p. F416-F420Article in journal (Refereed)
    Abstract [en]

    Palm F, Fasching A, Hansell P, K llskog. Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney. Am J Physiol Renal Physiol 298: F416-F420, 2010. First published November 18, 2009; doi: 10.1152/ajprenal.00229.2009.-Nitric oxide (NO) is a potent regulator of both vascular tone and cellular oxygen consumption (QO(2)). Diabetic kidneys have reduced NO availability and increased QO(2). However, the exact nitric oxide synthase (NOS) isoform regulating QO(2), hemodynamics, and excretory function in the diabetic kidney remains unclear. We therefore investigated the effects of both selective neuronal NOS (NOS1) inhibition and nonselective NOS inhibition. Oxygen utilization, electrolyte transport efficiency [tubular Na+ transport (T-Na)/QO(2)], renal blood flow (RBF), glomerular filtration rate (GFR), and mean arterial pressure (MAP) were measured in vivo in control and streptozotocin-diabetic rats before and after administration of the selective NOS1 inhibitor S-methyl-L-thiocitrulline (SMTC) or the nonselective NOS inhibitor N-G-nitro-L-arginine methyl ester (L-NAME). Diabetic rats had higher baseline QO(2) and GFR than control rats, although RBF was similar in the groups. SMTC and L-NAME increased QO(2) and reduced T-Na/QO(2) only in the diabetic animals, whereas both inhibitors increased MAP and reduced RBF in both groups. GFR was reduced by L-NAME, but SMTC had no effect in either group. Carbachol increased RBF and decreased MAP in SMTC-treated rats, whereas it had no effect in L-NAME-treated rats, indicating that SMTC selectively inhibited NOS1. In conclusion, NO regulates RBF and GFR similarly in both control and diabetic rats. However, selective NOS1 inhibition increased QO(2) and reduced T-Na/QO(2) in the diabetic rat kidney, indicating a pivotal role of NO produced by NOS1 in maintaining control of QO(2) and tissue oxygenation in these kidneys.

  • 14.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Friederich, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Teerlink, Tom
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Reduced nitric oxide in diabetic kidneys due to increased hepatic arginine metabolism: implications for renomedullary oxygen availability2008In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 294, no 1, p. F30-F37Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is a potent regulator of both vascular tone and oxygen utilization. Diabetes is commonly associated with both NO deficiency and reduced renomedullary oxygen availability. Arginine availability as regulator of NO production has gained growing interest. We hypothesized that arginine limitation causes diabetes-induced renomedullary NO deficiency, which directly influences renomedullary oxygen tension (P(o2)). Medullary NO, P(o2), and blood flow were measured in control and streptozotocin-induced diabetic rats, which were treated or not treated with alpha-tocopherol, and administered l-arginine followed by N(omega)-nitro-l-arginine methyl ester. Major components of arginine metabolism were also investigated. Diabetic rats had reduced renomedullary NO levels compared with controls. Arginine selectively increased NO levels in diabetic rats and totally restored NO levels in alpha-tocopherol-treated animals. Tocopherol prevented the reduction in medullary P(o2) in the diabetic animals. Although blood flow increased equally in all groups, arginine increased P(o2) exclusively in the diabetic groups. Diabetes decreased plasma arginine and asymmetric dimethylarginine concentrations, but increased hepatic CAT-2A and plasma ornithine independently of alpha-tocopherol treatment. In conclusion, diabetic rats had reduced renomedullary NO due to decreased plasma arginine following increased hepatic arginine uptake and degradation. This was unrelated to oxidative stress. The diabetes-induced reduction in renomedullary P(o2) was restored by either acute arginine administration, which also restored NO levels, or long-term antioxidant treatment. Arginine increased medullary NO and P(o2) independently of altered hemodynamics in the diabetic groups. This reveals a direct regulatory function of NO for renomedullary P(o2) especially during situations of elevated oxidative stress.

  • 15.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nangaku, Masaomi
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tanaka, Tetsuhiro
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kawakami, Takahisa
    Nishijima, Fuyuhiko
    Fujita, Toshiro
    Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress2010In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 299, no 2, p. F380-F386Article in journal (Refereed)
    Abstract [en]

    In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22(phox) showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.

  • 16. Papazova, Diana A.
    et al.
    Friederich-Persson, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Joles, Jaap A.
    Verhaar, Marianne C.
    Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension2015In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 308, no 1, p. F22-F28Article in journal (Refereed)
    Abstract [en]

    Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (PO2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney QO(2), cortical PO2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 +/- 3.3 vs. 0.9 +/- 0.4 pmol O-2.s(-1) .mg protein(-1), P < 0.05) and increased whole kidney Q(O2) (55 +/- 16 vs. 33 +/- 10 mu mol O-2/min, P < 0.05). Corticomedullary P-O2 was lower in TX compared with 1K-CON (30 +/- 13 vs. 47 +/- 4 mu M, P < 0.05) whereas no significant difference was observed between 2K-CON and 1K-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in 1K-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Q(O2), P-O2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage.

  • 17.
    Patinha, Daniela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pinho, Dora
    Albino-Teixeira, Antonio
    Morato, Manuela
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors2013In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 304, no 5, p. F614-F622Article in journal (Refereed)
    Abstract [en]

    Increased angiotensin II (ANG II) or adenosine can potentiate each other in the regulation of renal hemodynamics and tubular function. Diabetes is characterized by hyperfiltration, yet the roles of ANG II and adenosine receptors for controlling baseline renal blood flow (RBF) or tubular Na+ handling in diabetes is presently unknown. Accordingly, the changes in their functions were investigated in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of the ANG II AT(1) receptor antagonist candesartan, the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or their combination. Compared with controls, the baseline blood pressure, RBF, and renal vascular resistance (RVR) were similar in diabetics, whereas the glomerular filtration rate (GFR) and filtration fraction (FF) were increased. Candesartan, DPCPX, or the combination increased RBF and decreased RVR similarly in all groups. In controls, the GFR was increased by DPCPX, but in diabetics, it was decreased by candesartan. The FF was decreased by candesartan and DPCPX, independently. DPCPX caused the most pronounced increase in fractional Na+ excretion in both controls and diabetics, whereas candesartan or the combination only affected fractional Li+ excretion in diabetics. These results suggest that RBF, via a unifying mechanism, and tubular function are under strict tonic control of both ANG II and adenosine in both control and diabetic kidneys. Furthermore, increased vascular AT(1) receptor activity is a contribution to diabetes-induced hyperfiltration independent of any effect of adenosine A(1) receptors.

  • 18.
    Peleli, Maria
    et al.
    Dept of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Al-Mashhadi, Ammar Nadhom Farman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Yang, Ting
    Dept of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wåhlin, Nils
    Department of Pediatric surgery, Astrid Lindgren hospital, Karolinska Institutet, Stockholm, Sweden.
    Jensen, Boye L
    Dept of Physiology & Pharmacology, University of Southern Denmark, Odense, Denmark.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlström, Mattias
    Dept of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis2016In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 310, no 1, p. F43-F56Article in journal (Refereed)
    Abstract [en]

    Hydronephrosis is associated with development of salt-sensitive hypertension. Studies suggest that increased sympathetic nerve activity (SNA) and oxidative stress play important roles in renovascular hypertension. This study aimed to investigate the link between renal SNA and NADPH oxidase (NOX) regulation in the development of hypertension in rats with hydronephrosis. Hydronephrosis was induced by partial unilateral ureteral obstruction (PUUO) in young rats. Sham surgery or renal denervation was performed at the same time. Blood pressure was measured during normal, high and low salt diets. Renal excretion pattern, NOX activity and expression, as well as components of RAAS were characterized. On normal salt diet, PUUO rats had elevated blood pressure compared with controls (115±3 vs 87±1 mmHg), and displayed increased urine production and lower urine osmolality. Blood pressure change in response to salt loading (salt-sensitivity) was more pronounced in the PUUO group compared with controls (15±2 vs 5±1mmHg). Renal denervation in PUUO rats attenuated hypertension (97±3mmHg) and salt-sensitivity (5±1mmHg), and normalized renal excretion pattern, whereas the degree of renal fibrosis and inflammation was not changed. NOX activity and expression, as well as renin and AT1A receptor expression, were increased in renal cortex from PUUO rats, and normalized by denervation. Plasma sodium and potassium levels were elevated in PUUO rats and normalized after renal denervation. Denervation in PUUO rats was also associated with reduced NOX expression, superoxide production and fibrosis in the heart. This study emphasizes a link between renal nerves, NOX function, and development of hypertension.

  • 19.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Teerlink, Tom
    Vrije Univ Amsterdam, Med Ctr, Dept Clin Chem, Amsterdam, Netherlands.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Cellular transport of L-Arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity2017In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 312, no 2, p. F278-F283Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus is associated with decreased nitric oxide bioavailability thereby affecting renal blood flow regulation. Previous reports have demonstrated that cellular uptake of L-arginine is rate limiting for nitric oxide production, and that plasma L-arginine concentration is decreased in diabetes. We therefore investigated if regional renal blood flow regulation is affected by cellular L-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital and left kidney was exposed. Total, cortical and medullary renal blood flow was investigated before and after renal artery infusion of increasing doses of either L-homoarginine to inhibit cellular uptake of L-arginine, or L-NAME to inhibit nitric oxide synthase. L-homoarginine infusion did not affect total or cortical blood flow in any of the groups, but caused a dose-dependent reduction in medullary blood flow. L-NAME decreased total, cortical and medullary blood flow in both groups. However, the reductions in medullary blood flow in response to both L-homoarginine and L-NAME were more pronounced in the control groups compared to the diabetic groups. Isolated cortical tubular cells displayed similar L-arginine uptake capacity whereas medullary tubular cells isolated from diabetic rats had increased L-arginine uptake capacity. Diabetics had reduced L-arginine concentrations in plasma and medullary tissue but increased L-arginine concentration in cortical tissue. In conclusion, the reduced L-arginine availability in plasma and medullary tissue in diabetes results in reduced nitric oxide-mediated regulation of renal medullary hemodynamics. Cortical blood flow regulation displays less dependency on extracellular L-arginine and the upregulated cortical tissue L-arginine may protect cortical hemodynamics in diabetes.

  • 20. Tiwari, Swasti
    et al.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Halagappa, Veerendra K Madala
    Ecelbarger, Carolyn A
    Trafficking of ENaC subunits in response to acute insulin in mouse kidney2007In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 293, no 1, p. F178-F185Article in journal (Refereed)
    Abstract [en]

    Studies done in cell culture have demonstrated that insulin activates the epithelial sodium channel (ENaC) via a variety of mechanisms. However, to date, upregulation of ENaC in native renal tissue by in vivo administration of insulin has not been demonstrated. To address this, we injected 6-mo-old male C57BL/CBA mice (n = 14/group) intraperitoneally with vehicle or 0.5 U/kg body wt insulin and examined short-term (1-2 h) sodium excretion and kidney ENaC subunits (alpha, beta, and gamma) and serum and glucocorticoid-induced kinase (SGK-1) regulation. Insulin resulted in a significant reduction in urine sodium (by approximately 80%) that was restored by intraperitoneal administration of the ENaC antagonist, benzamil (1.4 mg/kg body wt). Differential centrifugation followed by Western blotting of whole kidney revealed significantly increased band densities (by 26-103%) for insulin- relative to vehicle-treated mice for alpha- and gamma-ENaC in the homogenate (H), and plasma membrane-enriched fraction (MF), with no difference in the vesicle-enriched fraction (VF). Similarly, beta-ENaC was significantly increased in MF (by 45%) but no change in the H. It was, however, significantly decreased in the VF (by 28%) with insulin. In agreement, immunoperoxidase labeling demonstrated relatively stronger apical, relative to cytosolic, localization of alpha-, beta-, and gamma-ENaC with insulin, whereas, with vehicle, labeling was fairly evenly dispersed throughout collecting duct principal cells. Furthermore, Western blotting showed insulin increased SGK-1 (by 75%) and phosphorylated-SGK band densities (by 30%) but only in the MF. These studies demonstrate novel in vivo regulation of renal ENaC activity and subunit proteins and SGK-1 by insulin in the acute time frame in the mouse.

  • 21.
    Turner, Anita J.
    et al.
    Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW, Australia.;Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia..
    Brown, Russell D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia.
    Brandon, Amanda E.
    Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia..
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia.
    Gibson, Karen J.
    Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia..
    Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes2017In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 313, no 4, p. F864-F873Article in journal (Refereed)
    Abstract [en]

    Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomcrular.filtration rate. or electrolyte excretion rates between the.Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex treatedfetuses was significantly lower (12.9 +/- 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 +/- 1.0 til/min). This resetting of TOE sensitivity persisted after birth (P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TOE sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TOE response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.

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