title: Cellular transport of l-arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity.
abstract: 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 whether regional renal blood flow regulation is affected by cellular l-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital, and the 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 Nω-nitro- l-arginine methyl ester (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 with 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.
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Patrik.Persson@mcb.uu.se.
authors.forename: Patrik
authors.initials: P
authors.lastname: Persson
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and.
authors.forename: Angelica
authors.initials: A
authors.lastname: Fasching
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Teerlink
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0002-0315-8554
authors.initials: P
authors.lastname: Hansell
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006709:Homoarginine / Q000494:pharmacology; D007679:Kidney Medulla / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D006709:Homoarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: cortical blood flow; kidney; l-homoarginine; renal blood flow; streptozotocin