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

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 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 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 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 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.