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Publications (10 of 49) Show all publications
Zhou, S., Jiang, S., Guo, J., Xu, N., Wang, Q., Zhang, G., . . . Lai, E. Y. (2019). ADAMTS13 protects mice against renal ischemia-reperfusion injury by reducing inflammation and improving endothelial function. American Journal of Physiology - Renal Physiology, 316(1), F134-F145
Open this publication in new window or tab >>ADAMTS13 protects mice against renal ischemia-reperfusion injury by reducing inflammation and improving endothelial function
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2019 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 1, p. F134-F145Article in journal (Refereed) Published
Abstract [en]

Acute kidney injury (AKI) is a serious condition without efficient therapeutic options. Recent studies have indicated that recombinant human a disintegrin and metalloprotease with thrombospondin motifs 13 (rhADAMTS13) provides protection against inflammation. Therefore, we hypothesized that ADAMTS13 might protect against AKI by reducing inflammation. Bilateral renal ischemia-reperfusion injury (I/R) was used as AKI models in this study. Prophylactic infusion of rhADAMTS13 was employed to investigate potential mechanisms of renal protection. Renal function, inflammation, and microvascular endothelial function were assessed after 24 h of reperfusion. Our results showed that I/R mice increased plasma von Willebrand factor levels but decreased ADAMTS13 expression. Administration of rhADAMTS13 to I/R mice recovered renal function, histological injury, and apoptosis. Renal inflammation was reduced by rhADAMTS13, accompanied with the downregulation of p38/extracellular signal-regulated protein kinase phosphorylation and cyclooxygenase-2 expression. rhADAMTS13 restored vasodilation in afferent arterioles in I/R mice. Furthermore, rhADAMTS13 treatment enhanced phosphorylation of Akt at Set(473) and eNOS at Ser(1177). Administration of the Akt pathway inhibitor wortmannin reduced the protective effect of rhADAMTS13. Our conclusions are that treatment with rhADAMTS13 ameliorates renal I/R injury by reducing inflammation, tubular cell apoptosis. and improving microvascular endothelial dysfunction. rhADAMIS13 could be a promising strategy to treat AKI in clinical settings.

Keywords
acute kidney injury, endothelial dysfunction, ischemia and reperfusion, rhADAMTS13
National Category
Urology and Nephrology Physiology
Identifiers
urn:nbn:se:uu:diva-375849 (URN)10.1152/ajprenal.00405.2018 (DOI)000455616200014 ()30461292 (PubMedID)
Funder
Swedish Society of MedicineSwedish Heart Lung FoundationGerman Research Foundation (DFG), DFG PA 479/10-1; PA 479/10-2
Available from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically approved
Fähling, M., Paliege, A., Jönsson, S., Becriovic Agic, M., Melville, J. M., Skogstrand, T. & Hultström, M. (2019). NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats. American Journal of Physiology - Renal Physiology, 316(1), F101-F112
Open this publication in new window or tab >>NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats
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2019 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 1, p. F101-F112Article in journal (Refereed) Published
Abstract [en]

The aim was to identify new targets that regulate gene expression at the posttranscriptional level in angiotensin II (ANGII)-mediated hypertension. Heparin affinity chromatography was used to enrich nucleic acid-binding proteins from kidneys of two-kidney, one-clip (2K1C) hypertensive Wistar rats. The experiment was repeated with 14-day ANGII infusion using Alzet osmotic mini pumps. with or without ANGII receptor AT1a inhibition using losartan in the drinking water. Mean arterial pressure increased after 2K1C or ANGII infusion and was inhibited with losartan. Heparin affinity chromatography and mass spectrometry were used to identify Annexin-A2 (ANXA2) as having differential nucleic acid-binding activity. Total Annexin-A2 protein expression was unchanged, whereas nucleic acid-binding activity was increased in both kidneys of 2K1C and after ANGII infusion through AT1a stimulation. Costaining of Annexin-A2 with alpha-smooth muscle actin and aquaporin 2 showed prominent expression in the endothelia of larger arteries and the cells of the inner medullary collecting duct. The nuclear factor of activated T cells (NFAT) transcription factor was identified as a likely Annexin-A2 target using enrichment analysis on a 2K1C microarray data set and identifying several binding sites in the regulatory region of the mRNA. Expression analysis showed that ANGII increases NFAT5 protein but not mRNA level and, thus, indicated that NFAT5 is regulated by posttranscriptional regulation, which correlates with activation of the RNA-binding protein Annexin-A2. In conclusion, we show that ANGII increases Annexin-A2 nucleic acid-binding activity that correlates with elevated protein levels of the NFAT5 transcription factor. NFAT signaling appears to be a major contributor to renal gene regulation in high-renin states.

Keywords
angiotensin II, annexin-A2, hypertension, kidney damage, NFAT
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-375848 (URN)10.1152/ajprenal.00361.2018 (DOI)000455616200010 ()30332317 (PubMedID)
Funder
Magnus Bergvall FoundationSwedish Society of Medicine
Available from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically approved
Hultström, M., Becriovic-Agic, M. & Jönsson, S. (2018). Comparison of acute kidney injury of different aetiology reveals in-common mechanisms of tissue damage. Physiological Genomics, 50(3), 127-141
Open this publication in new window or tab >>Comparison of acute kidney injury of different aetiology reveals in-common mechanisms of tissue damage
2018 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 50, no 3, p. 127-141Article, review/survey (Refereed) Published
Abstract [en]

Acute kidney injury (AKI) is a syndrome of reduced glomerular filtration rate (GFR) and urine production caused by a number of different diseases. It is associated with renal tissue damage. This tissue damage can cause tubular atrophy and interstitial fibrosis that leads to nephron loss and progression of chronic kidney disease (CKD). This review describes the in-common mechanisms behind tissue damage in AKI caused by different underlying diseases. Comparing six high-quality microarray studies of renal gene expression after AKI in disease models (gram-negative sepsis, gram-positive sepsis, ischemia-reperfusion, malignant hypertension, rhabdomyolysis and cisplatin toxicity) identified 5254 differentially expressed genes in at least one of the AKI models. 66% of genes were only found in one model showing that there are unique features to AKI depending on the underlying disease. There were in-common features in the form of four genes that were differentially expressed in all six models, 49 in at least five, and 215 were in-common between at least four models. Gene ontology enrichment analysis could be broadly categorized into the injurious processes hypoxia, oxidative stress, and inflammation, as well as the cellular outcomes of cell death and tissue remodeling in the form of epithelial to mesenchymal transition (EMT). Pathway analysis showed that MYC is a central connection in the network of activated genes in-common to AKI, which suggests that it may be a central regulator of renal gene expression in tissue injury during AKI. The outlining of this molecular network may be useful for understanding progression from AKI to CKD.

Keywords
acute kidney injury, biomarker, gene expression, molecular, tissue injury
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-340389 (URN)10.1152/physiolgenomics.00037.2017 (DOI)000428814500001 ()29341864 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-01-29 Created: 2018-01-29 Last updated: 2019-02-01Bibliographically approved
Weigl, W., Adamski, J., Goryński, P., Kański, A. & Hultström, M. (2018). ICU mortality and variables associated with ICU survival in Poland: A nationwide database study. European Journal of Anaesthesiology, 35(12), 949-954
Open this publication in new window or tab >>ICU mortality and variables associated with ICU survival in Poland: A nationwide database study
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2018 (English)In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 35, no 12, p. 949-954Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Recently published international comparison data across European countries revealed high mortality rates in Polish ICUs.

OBJECTIVES: Estimation of the rate of ICU mortality and identification of variables associated with ICU survival in Poland.

DESIGN: Retrospective analyses of a database reporting ICU stays in Poland.

SETTINGS AND PATIENTS: The study included data from all adult patients admitted to an ICU in Poland from 1 January 2012 to 31 December 2012.

MAIN OUTCOME MEASURES: ICU mortality and variables associated with ICU survival.

RESULTS: A total of 48 282 patients were treated in 347 ICUs (mean age 63.1 ± 16.8 years, 59% men) with 20 278 deaths (42.0%). Variables associated with ICU survival were: tertiary level of hospital care [relative risk (RR) 0.86, 95% confidence interval (CI) 0.80 to 0.92, P < 0.001]; high annual patient volume in the ICU (RR 0.9995 patient year, 95% CI 0.9994 to 0.9996, P < 0.001); younger patient age (RR 1.025 year, 95% CI 1.024 to 1.026, P < 0.001); female sex (RR 0.92, 95% CI 0.88 to 0.96; P < 0.001); and lower number of comorbidities (RR 1.33, 95% CI 1.31 to 1.35, P < 0.001).

CONCLUSION: ICU mortality was high in Poland. Structural variables, such as the level of hospital care and annual patient volume, may be associated with ICU survival.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-361211 (URN)10.1097/EJA.0000000000000889 (DOI)000455899400008 ()30234666 (PubMedID)
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2019-02-07Bibliographically approved
Jönsson, S., Melville, J. M., Agic, M. B. & Hultström, M. (2018). Losartan does not decrease renal oxygenation and norepinephrine effects in rats after resuscitated hemorrhage.. American Journal of Physiology - Renal Physiology, 315(2), F241-F246
Open this publication in new window or tab >>Losartan does not decrease renal oxygenation and norepinephrine effects in rats after resuscitated hemorrhage.
2018 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 315, no 2, p. F241-F246Article in journal (Refereed) Published
Abstract [en]

Renin-angiotensin-system blockers are thought to increase the risk of acute kidney injury after surgery and hemorrhage. We found that losartan does not cause renal cortical hypoxia after hemorrhage in rats because of decreased renal vascular resistance, but we did not evaluate resuscitation. We aimed to study losartan's effect on renal cortical and medullary oxygenation, as well as norepinephrine's vasopressor effect in a model of resuscitated hemorrhage. After 7 days of losartan (60 mg·kg-1·day-1) or control treatment, male Wistar rats were hemorrhaged 20% of their blood volume and resuscitated with Ringer's acetate. Mean arterial pressure, renal blood flow, and kidney tissue oxygenation were measured at baseline and after resuscitation. Finally, the effect of norepinephrine on mean arterial pressure and renal blood flow was investigated. As expected, losartan lowered mean arterial pressure but not renal blood flow. Losartan did not affect renal oxygen consumption and oxygen tension. Mean arterial pressure and renal blood flow were lower after resuscitated hemorrhage. A smaller increase of renal vascular resistance in the losartan group translated to a smaller decrease in cortical oxygen tension, but no significant difference was seen in medullary oxygen tension, either between groups or after hemorrhage. The effect of norepinephrine on mean arterial pressure and renal blood flow was similar in control- and losartan-treated rats. Losartan does not decrease renal oxygenation after resuscitated hemorrhage because of a smaller increase in renal vascular resistance. Further, losartan does not decrease the efficiency of norepinephrine as a vasopressor, indicating that blood pressure may be managed effectively during losartan treatment.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-361202 (URN)10.1152/ajprenal.00095.2018 (DOI)000441092800006 ()29667909 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2019-02-01Bibliographically approved
Zhang, S., Huang, Q., Cai, X., Jiang, S., Xu, N., Zhou, Q., . . . Lai, E. Y. (2018). Osthole Ameliorates Renal Fibrosis in Mice by Suppressing Fibroblast Activation and Epithelial-Mesenchymal Transition. Frontiers in Physiology, 9, Article ID 1650.
Open this publication in new window or tab >>Osthole Ameliorates Renal Fibrosis in Mice by Suppressing Fibroblast Activation and Epithelial-Mesenchymal Transition
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2018 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1650Article in journal (Refereed) Published
Abstract [en]

Renal fibrosis is a common pathway of virtually all progressive kidney diseases. Osthole (OST, 7-Methoxy-8-(3-methylbut-2-enyl)-2-chromenone), a derivative of coumarin mainly found in plants of the Apiaceae family, has shown inhibitory effects on inflammation, oxidative stress, fibrosis and tumor progression. The present study investigated whether OST mediates its effect via suppressing fibroblast activation and epithelial-mesenchymal transition (EMT) in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Herein, we found that OST inhibited fibroblast activation in a dose-dependent manner by inhibiting the transforming growth factor-beta 1 (TGF beta 1)-Smad pathway. OST also blocked fibroblast proliferation by reducing DNA synthesis and downregulating the expressions of proliferation- and cell cycle-related proteins including proliferating cell nuclear antigen (PCNA), CyclinD1 and p21 Waf1/Cip1. Meanwhile, in the murine model of renal interstitial fibrosis induced by UUO, myofibroblast activation with increased expression of alpha-smooth muscle actin (alpha-SMA) and proliferation were attenuated by OST treatment. Additionally, we provided in vivo evidence suggesting that OST repressed EMT with preserved E-cadherin and reduced Vimentin expression in obstructed kidney. UUO injury-induced upregulation of EMT-related transcription factors, Snail family transcriptional repressor-1(Snail 1) and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist) as well as elevated G2/M arrest of tubular epithelial cell, were rescued by OST treatment. Further, OST treatment reversed aberrant expression of TGF beta 1-Smad signaling pathway, increased level of proinflammatory cytokines and NF-kappaB (NF-kappa B) activation in kidneys with obstructive nephropathy. Taken together, these findings suggest that OST hinder renal fibrosis in UUO mouse mainly through inhibition of fibroblast activation and EMT.

Keywords
osthole, fibroblast, EMT, inflammation, renal fibrosis
National Category
Cell and Molecular Biology Physiology
Identifiers
urn:nbn:se:uu:diva-371049 (URN)10.3389/fphys.2018.01650 (DOI)000450947300001 ()
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-01-07Bibliographically approved
Colldén, J., Hultström, M. & Birgisdottir, B. (2017). Case of subdural hematoma after labor epidural: implications for follow-up of post dural puncture head ache. Acta Anaesthesiologica Scandinavica, 61(8), 985-985
Open this publication in new window or tab >>Case of subdural hematoma after labor epidural: implications for follow-up of post dural puncture head ache
2017 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 985-985Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-342124 (URN)000407231100048 ()
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-02-22Bibliographically approved
Wang, R., Zhang, W., Dong, Z., Qi, Y., Hultström, M., Zhou, X. & Lai, E. Y. (2017). c-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression. Acta Physiologica, 219(2), 494-509
Open this publication in new window or tab >>c-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression
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2017 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 219, no 2, p. 494-509Article in journal (Refereed) Published
Abstract [en]

AIM: Prostaglandin E2 mediates sympathoexcitation in chronic heart failure (CHF) through EP3 receptors (PTGER3) in the paraventricular nucleus (PVN). The aim of this study was to investigate the role of c-Jun N-terminal kinase (JNK) in expressional regulation of gamma-aminobutyric acid signalling in PVN in CHF rats.

METHODS: Chronic heart failure was induced by left coronary ligation in Wistar rats. Renal sympathetic nerve discharge (RSND) and mean arterial pressure (MAP) responses to the PVN infusion were determined in anaesthetized rats. Osmotic minipumps were used for chronic PVN infusion. PTGER3 expression was examined with immunofluorescence staining, quantitative real-time PCR and Western blot.

RESULTS: Chronic heart failure rats had increased JNK activation and decreased glutamate decarboxylase 1 (GAD1) and GABAA receptor alpha 1 subunit (GABRA1) expression in the PVN. PVN infusion of the PTGER3 agonist SC-46275 caused sympathoexcitation in sham-operated control (Sham) rats and increased it further in CHF. The PTGER3 antagonist L798106 reduced sympathoexcitation and cardiac dysfunction in CHF. PVN infusion of EP1 receptor antagonist SC-19220, EP2 receptor antagonist AH6809 or EP4 receptor antagonist L-161982 had no effect on sympathoexcitation. The JNK inhibitor SP600125 normalized sympathoexcitation and GAD1 and GABRA1 expression in PVN in CHF rats. Both the p44/42 and p38 mitogen-activated protein kinase inhibitors PD98059 and SB203580 could not prevent the downregulation of GAD1 and GABRA1 expression in PVN in CHF. PTGER3 agonist activated JNK but downregulated GAD1 and GABRA1 expression in NG108 neuronal cells.

CONCLUSION: Prostaglandin signalling through upregulated PTGER3 activates JNK which reduces GAD1 and GABRA1 expression in the PVN, and contributes to sympathoexcitation in CHF.

Keywords
EP3 receptor, c-Jun N-terminal kinase, chronic heart failure, paraventricular nucleus, sympathetic nerve discharge
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-318019 (URN)10.1111/apha.12758 (DOI)000393912000014 ()27439062 (PubMedID)
Funder
Swedish Heart Lung Foundation
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-01-13Bibliographically approved
Weigl, W., Adamski, J., Gorynski, P., Kanski, A. & Hultström, M. (2017). Comparison of ICU outcomes in Poland to other European countries: reasons for high mortality rates. Acta Anaesthesiologica Scandinavica, 61(8), 1022-1023
Open this publication in new window or tab >>Comparison of ICU outcomes in Poland to other European countries: reasons for high mortality rates
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2017 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 1022-1023Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-342128 (URN)000407231100106 ()
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-02-22Bibliographically approved
Becriovic Agic, M., Jönsson, S. & Hultström, M. (2017). Genetic association of oxidative stress and fluid accumulation makes Balb/CJ mice more sensitive to decompensated heart failure. Acta Anaesthesiologica Scandinavica, 61(8), 963-964
Open this publication in new window or tab >>Genetic association of oxidative stress and fluid accumulation makes Balb/CJ mice more sensitive to decompensated heart failure
2017 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 963-964Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-342121 (URN)000407231100016 ()
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2019-02-01Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-4675-1099

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