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EDITORIAL FOCUS

Reduced nitric oxide in diabetic kidneys due to increased hepatic arginine metabolism: implications for renomedullary oxygen availability

Departments of ¹Medical Cell Biology, ²Medical Sciences, and ⁴Oncology, Radiology, and Clinical Immunology, Uppsala University, Uppsala, Sweden; and ³Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

Submitted 10 April 2007 ; accepted in final form 15 October 2007

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 (PO₂). Medullary NO, PO₂, and blood flow were measured in control and streptozotocin-induced diabetic rats, which were treated or not treated with -tocopherol, and administered L-arginine followed by N-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 -tocopherol-treated animals. Tocopherol prevented the reduction in medullary PO₂ in the diabetic animals. Although blood flow increased equally in all groups, arginine increased PO₂ exclusively in the diabetic groups. Diabetes decreased plasma arginine and asymmetric dimethylarginine concentrations, but increased hepatic CAT-2A and plasma ornithine independently of -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 PO₂ was restored by either acute arginine administration, which also restored NO levels, or long-term antioxidant treatment. Arginine increased medullary NO and PO₂ independently of altered hemodynamics in the diabetic groups. This reveals a direct regulatory function of NO for renomedullary PO₂ especially during situations of elevated oxidative stress.

diabetes mellitus; blood flow; plasma arginine; asymmetric dimethylarginine; oxidative stress; vationic amino acid transporter