Prevention of apoptotic onset rescues from glomerular tubular disconnection and podocyte loss in proteinuric kidney disease

There is a great need for treatment that arrests progression of chronic kidney disease. Increased albumin in primary urine leads to apoptosis and fibrosis of podocytes and tubular cells and is a major cause of functional deterioration. There have been many attempts to target fibrosis but few to target apoptosis, because of lack of appropriate agents. Our group has described an ouabain activated Na,K-ATPase/IP3R signalosome, which protects from apoptosis. Here we show that albumin uptake in primary rat renal epithelial cells is accompanied by a time and dose dependent mitochondrial accumulation of the apoptotic factor Bax, down-regulation of the anti-apoptotic factor Bcl-xL and mitochondrial membrane depolarization. Ouabain opposes these effects and protects from apoptoss in albumin-exposed proximal tubule cells and podocytes. The efficacy of ouabain as an anti-apoptotic and kidney-protective therapeutic tool is tested in rats with passive Heymann nephritis, a model of proteinuric chronic kidney disease. Chronic ouabain treatment preserves renal function, protects from renal cortical apoptosis, up-regulation of Bax, down-regulation of Bcl-xL and rescues from glomerular tubular disconnection and podocyte loss. Thus we have identified a novel clinically feasible therapeutic tool, which has the potential to protect from apoptosis and rescue from loss of functional tissue in chronic proteinuric kidney disease.