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L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
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2014 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 2, 323-329 p.Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus–induced oxidative stress causes increased renal oxygen consumption and intrarenal tissue hypoxia. Nitric oxide is an important determinant of renal oxygen consumption and electrolyte transport efficiency. The present study investigates whether l-arginine or l-citrulline to promote nitric oxide production prevents the diabetes mellitus–induced kidney dysfunction. Glomerular filtration rate, renal blood flow, in vivo oxygen consumption, tissue oxygen tension, and proteinuria were investigated in control and streptozotocin-diabetic rats with and without chronic l-arginine or l-citrulline treatment for 3 weeks. Untreated and l-arginine–treated diabetic rats displayed increased glomerular filtration rate (2600±162 versus 1599±127 and 2290±171 versus 1739±138 µL/min per kidney), whereas l-citrulline prevented the increase (1227±126 versus 1375±88 µL/min per kidney). Filtration fraction was increased in untreated diabetic rats because of the increase in glomerular filtration rate but not in l-arginine– or l-citrulline–treated diabetic rats. Urinary protein excretion was increased in untreated and l-arginine–treated diabetic rats (142±25 versus 75±7 and 128±7 versus 89±7 µg/min per kidney) but not in diabetic rats administered l-citrulline (67±7 versus 61±5 µg/min per kidney). The diabetes mellitus–induced tissue hypoxia, because of elevated oxygen consumption, was unaltered by any of the treatments. l-citrulline administered to diabetic rats increases plasma l-arginine concentration, which prevents the diabetes mellitus–induced glomerular hyperfiltration, filtration fraction, and proteinuria, possibly by a vascular effect.

Place, publisher, year, edition, pages
2014. Vol. 64, no 2, 323-329 p.
National Category
Physiology Basic Medicine
Research subject
Medical Science; Physiology
URN: urn:nbn:se:uu:diva-195487DOI: 10.1161/HYPERTENSIONAHA.114.03519ISI: 000339120700023PubMedID: 24866144OAI: oai:DiVA.org:uu-195487DiVA: diva2:607663
Available from: 2013-02-25 Created: 2013-02-25 Last updated: 2014-08-19Bibliographically approved
In thesis
1. Aspects of Regulation of GFR and Tubular Function in the Diabetic Kidney: Roles of Adenosine, Nitric Oxide and Oxidative Stress
Open this publication in new window or tab >>Aspects of Regulation of GFR and Tubular Function in the Diabetic Kidney: Roles of Adenosine, Nitric Oxide and Oxidative Stress
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetic nephropathy is the main cause for initiation of renal replacement therapy and early symptoms in patients include increased glomerular filtration rate (GFR), decreased oxygen tension and albuminuria, followed by a progressive decline in GFR and loss of kidney function. Experimental models of diabetes display increased GFR, decreased tissue oxygenation and nitric oxide bioavailability. These findings are likely to be intertwined in a mechanistic pathway to kidney damage and this thesis investigated their roles in the development of diabetic nephropathy. In vivo, diabetes-induced oxidative stress stimulates renal tubular Na+ transport and in vitro, proximal tubular cells from diabetic rats display increased transport-dependent oxygen consumption, demonstrating mechanisms contributing to decreased kidney oxygenation. In control animals, endogenous adenosine reduces vascular resistance of the efferent arteriole via adenosine A2-receptors resulting in reduced filtration fraction. However, in diabetes, adenosine A2-signalling is dysfunctional resulting in increased GFR via increased filtration fraction. This is caused by reduced adenosine A2a receptor-mediated vasodilation of efferent arterioles. The lack of adenosine-signaling in diabetes is likely due to reduced local adenosine concentration since adenosine A2a receptor activation reduced GFR only in diabetic animals by efferent arteriolar vasodilation. Furthermore, sub-optimal insulin treatment also alleviates increased filtration pressure in diabetes. However, this does not affect GFR due to a simultaneously induction of renal-blood flow dependent regulation of GFR by increasing the filtration coefficient. In diabetes, there is decreased bioavailability of nitric oxide, resulting in alterations that may contribute to diabetes-induced hyperfiltration and decreased oxygenation. Interestingly, increased plasma concentration of l-arginine, the substrate for nitric oxide production, prevents the development of increased GFR and proteinuria, but not increased oxygen consumption leading to sustained intra-renal hypoxia in diabetes. This thesis concludes that antioxidant treatment directed towards the NADPH oxidase as well maneuvers to promote nitric oxide production is beneficial in diabetic kidneys but is targeting different pathways i.e. transport-dependent oxygen consumption in the proximal tubule by NADPH oxidase inhibition and intra-renal hemodynamics after increased plasma l-arginine. Also, the involvement and importance of efferent arteriolar resistance in the development of diabetes-induced hyperfiltration via reduced adenosine A2a signaling is highlighted.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 871
diabetes, diabetic nephropathy, glomerular filtration rate, renal blood flow, insulin, renal hemodynamics, micropuncture, oxygen, NADPH-oxidase, apocynin, streptozotocin, l-arginine, CGS21680, rats, mice
National Category
Research subject
Physiology; Medical Science
urn:nbn:se:uu:diva-195956 (URN)978-91-554-8610-5 (ISBN)
Public defence
2013-04-19, A1:107a, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Available from: 2013-03-26 Created: 2013-03-01 Last updated: 2013-04-02Bibliographically approved

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