Diabetic nephropathy: nitric oxide and renal medullary hypoxia

Abstract

DIABETES, SPECIFICALLY DIABETIC nephropathy, is the most frequent cause of end-stage renal disease (ESRD) in developed countries (10). Classically, studies into the mechanisms underlying diabetic nephropathy have focused on glomerular injury and the development of albuminuria; however, changes in tubulointerstitial structure and function are also evident even during the early stages in diabetes (3, 4, 11, 13, 14, 16). Changes in proximal tubule structure consistent with hypertrophy (increases in cell height, tubule diameter, and length) are a prominent component of diabetic renal hypertrophy, with other nephron segments also displaying changes in tubule length (13, 14). There is evidence of altered renal handling of electrolytes, including Na, and increased renal Na-KATPase (NKA) activity has been widely reported in diabetes. The changes in NKA activity accompanying type 1 diabetes mellitus coincide with, and thus may play a role in, the development of hypertrophy. On the other hand, as NKAmediated ion transport is the major consumer of metabolic energy in the kidney, the early and pronounced increase in tubular NKA activity in diabetes has been proposed to represent an important adaptive response to the osmotic diuresis (4, 16) and/or the chronic increase in filtered Na load. Upregulation of NKA activity is particularly evident in the outer medulla (3, 4, 16), where low blood flow limits O2 supply despite high O2 consumption coupled with reabsorptive Na transport. As O2 extraction is almost maximal under normal conditions in the outer medulla, the increased NKA activity linked to increased Na transport during diabetes is accompanied by reduced PO2 in this region that normally exists near the brink of hypoxia. Thus diabetes would promote chronic hypoxia, which may be a common pathway leading to ESRD (8). In the healthy kidney, the renal medulla has high concentrations of nitric oxide (NO) (18). Reduced NO bioavailability has been shown to result in increased O2 consumption and, therefore, increased sodium reabsorption in the renal medulla (2, 5). Diabetes is known to be a condition of oxidative stress and reduced NO bioavailability. Little information is available in the literature pertaining to the status of NO and O2 availability in the renal medulla during diabetes. Palm and colleagues (12) have begun to unravel the complex mechanisms involved in the interrelationship between reduced NO bioavailability and hypoxia in the renal medulla in the early stages of diabetes. Palm et al. (12) report that reduced renal medullary NO levels in diabetes are due to decreased plasma L-arginine and unrelated to diabetes-induced oxidative stress, while the reduction in medullary PO2 was restored by L-arginine administration or antioxidant treatment. The authors also observed that the O2 availability in both normal and diabetic rats was independent of blood flow alterations. These observations underscore the potential importance of diabetes-induced renal metabolic alterations and their functional consequences. At physiological concentrations, NO inhibits the mitochondrial enzyme cytochrome c oxidase (complex IV) in competi