Nitric oxide deficiency in chronic renal disease

Abstract

There is clear evidence that chronic inhibition of nitric oxide synthase (NOS) in animals causes hypertension and also leads to progressive kidney damage. There is also evidence that nitric oxide (NO) deficiency occurs in man with chronic kidney disease (CRD) and this may contribute to further progression of CRD, to hypertension, and to other cardiovascular complications. There are multiple ways in which NO deficiency develops in CRD. At end stage there are uremic factors in plasma that inhibit L-arginine transport into cells and this may cause a “net” substrate deficiency. Also, increases occur in endogenous NOS inhibitors, in particular asymmetric dimethylarginine (ADMA). The increased oxidative stress of CRD is likely to be a primary cause of the increased plasma ADMA since the catabolic enzyme, dimethylarginine dimethylaminohydrolase (DDAH) is extremely sensitive to inhibition by oxidants. Animal studies demonstrate a decrease in abundance of the neuronal NOS within the injured kidney that correlates with extent of injury. Overall, there is substantial clinical, “in vitro,” and animal data to suggest that systemic, endothelial, and renal NO deficiency is a common feature of CRD irrespective of the primary genesis of the disease. This NO deficiency, which is multifactorial, contributes to the progressive nature of the CRD and the endothelial dysfunction and associated risk for cardiovascular events. Strategies that reverse NOS inhibition and/or can boost the ability of the damaged kidney to produce NO might help preserve residual renal function and/or slow down the rate of progression to end stage.