Pathomechanism of diabetic nephropathy

Abstract: Diabetic nephropathy is today the most common cause of end stage renal failure. The risk for developing overt diabetic nephropathy is considerably reduced by antihypertensive treatment, and adequate control of blood glucose. However, there is a need for additional and even more efficient tools to prevent this complication of diabetes. The purpose of this thesis has therefore been 1. To gain more information on the mechanisms behind one of the factors believed to contribute to the development of hypertension, namely sodium retention and 2. To examine the effects of 2 drugs that may restore some of the metabolic perturbations caused by hyperglycemia, namely the increased formation of sorbitol from glucose via aldose reductase and the development of oxidative stress. The studies have been performed in rats with streptozotocin induced diabetes. Various pararneters of renal function, known to be altered in diabetes, were determined 2 to 12 weeks after the induction of diabetes. It was found that 1. Hyperglycernia is the primary cause of sodium retention in diabetes, since it causes increased reabsorption of Na via the Na/glucose cotransporter in the proximal tubule This effect was also found to contribute to diabetic hyperfiltration. In rats with a genetic predisposition for sodium retention and salt sensitive hypertension, the rate of developing diabetic nephropathy was considerably increased. 2. Aldose reductase inhibitors did not, in the doses applied in my studies, have any effect on the renal functional disturbances in the diabetic rats. In contrast, nitecapone, a very potent antioxidant, completely abolished the early functional disturbances and attenuated the development of glomerulosclerosis. Administration of nitecapone also intestinal hypomotility, which is likely a manifestation of diabetes-induced disturbances of the autonomous nervous system. - Prostaglandins have also been implicated in the pathogenesis of diabetic nephropathy. In a clinical study we found no effect of prostaglandin synthesis inhibition on renal function and albumin excretion rate in young diabetic women. In conclusion, this study has indicated both sodium retention and oxidative stress will significantly contribute to the development of diabetic nephropathy, and more attempts should therefore be made to alleviate these metabolic disturbances. Interestingly, both sodium retention and oxidative stress appear to be the consequences of hyperglycemia.