Is renal Na+,K+‐ATPase a new target for renin–angiotensin blocking agents in diabetic nephropathy?

Abstract

Diabetic nephropathy is a clinical syndrome characterized by increasing arterial blood pressure, albuminuria and a relentless decline in renal function. It is the leading cause of end-stage renal failure in the western world and the incidence of end-stage renal disease due to diabetes has been increasing dramatically during the past 20 years. Furthermore, patients suffering from diabetic nephropathy have an increased risk of cardiovascular morbidity and mortality. It has been demonstrated that optimized glycaemic control and aggressive antihypertensive treatment with particular focus on the renin–angiotensin system (RAS) blockers have reduced the individual patient risk for development and progression of diabetic nephropathy (Rossing, 2005). An important aspect of the development of diabetic nephropathy is the inappropriately activated renin–angiotensin system, and fluid and sodium retention contributing to the development of hypertension and renal damage (Feldt-Rasmussen et al. 1987). An understanding of the physiology leading to these changes could potentially improve the prevention and treatment of this important complication. In this context Fekete and colleagues (Fekete et al. 2008) demonstrate, in this issue of The Journal of Physiology, that STZ-diabetes in rats increases the mRNA expression, protein level, Ser23 phosphorylation and enzyme activity of renal Na+,K+-ATPase (NKA) which is further elevated by a pressor dose of angiotensin II (ANGII) for 24 h. The NKA is important for the regulation of the fluid and sodium potassium balance by extruding sodium from the basolateral membrane in proximal tubuli. It is, however, also demonstrated in their study that although the abundance and activity of renal NKA is increased, the channels may no longer be functional as they are to some extent redistributed from the basolateral membrane to the cytosol in diabetic animals and even more so when ANGII is added. Whether this is the result of an adaptive response to increased filtered Na+ or a cause of the disturbed Na+ balance is not studied. Thus, a potentially important effect of both chronic hyperglycaemia and acute ANGII on NKA activity and location is demonstrated. The authors speculate if this is a new mechanism contributing to the development of renal disease in diabetes and furthermore, it is suggested that prevention of the ANGII-induced changes described in the study could be a new explanation of part of the beneficial effect of RAS blocking pharmacological intervention in diabetic nephropathy which has been demonstrated in many clinical trials. So far this has been attributed to ANGII effects on haemodynamic (systemic and intrarenal blood pressure) and non-haemodynamic factors (such as effects on growth factors, PAI-1, nephrin, inflammation, glomerular pore size and charge selectivity). The mechanisms for the hyperglycaemia and ANGII-induced effects are not studied, and although they may act through different pathways, a common pathway is also possible. Recently Peti-Peterdi et al. (2008) described how elevated glucose metabolized to elevated levels of succinate, which activates the GPR91 receptor in the juxtaglomerular apparatus (JGA) leading to subsequent release of renin in the JGA. Thus, a link between hyperglycaemia and activation of the renin–angiotensin system was demonstrated. Therefore, RAS blockade could potentially block the effect of hyperglycaemia as well as the effect of non-hyperglycaemia-related RAS activation. Additional studies of the effect of RAS blockade on NKA activation and redistribution in diabetes could help us understanding if hyperglycaemia induces the changes through activation of the renin–angiotensin system, and further evaluation of diabetes with additional stress activating the RAS would help us to understand if the observation by Fekete and colleagues (Fekete et al. 2008) is indeed a new mechanism explaining the beneficial effect of RAS intervention in preventing and treating diabetic nephropathy. It would also be important to evaluate the effect on renal NKA activity and localization of RAS activation through dietary sodium restriction or diuretic treatment, demonstrated to enhance the clinical efficacy of RAS blocking agents. Thus, as with any good study, the paper by Fekete et al. provides new and interesting knowledge related to the problem of sodium and fluid retention in diabetic nephropathy, potentially contributing to the development of diabetic glomerulosclerosis, and thus a potential target for intervention. However, the study also raises new questions which need to be explored before we will know if an effect on renal NKA by RAS blocking agents affects the development of diabetic nephropathy.