Inhibition of MAPK P38 Decreases Hyperglycemia-Induced Nephrin Endocytosis and Protects Against Proteinuria

Diabetic nephropathy is the leading cause of end stage renal disease. In diabetes albuminuria is an early sign of a leaky renal filter and leads to an accelerated loss of renal function. Despite intensive research there is still no specific antiproteinuric therapy available. Thus, deeper understanding of the molecular mechanisms of albuminuria is desirable. MAPK p38 signaling has been shown to be involved in the development of hyperglycemia-induced albuminuria; however, it remains unclear how increased p38 activity leads to loss of albumin in the urine. We recently demonstrated that acute hyperglycemia triggers endocytosis of nephrin, the key molecule of the slit diaphragm, and induces albuminuria. Here, we identify p38 as pivotal regulator of hyperglycemia-induced nephrin endocytosis and proteinuria. Activated p38 phosphorylates the nephrin c-terminus at serine 1146, facilitating the interaction of PKCα with nephrin. PKCα phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of β-arrestin2 to nephrin. β-arrestin2 triggers endocytosis of nephrin by coupling it to the endocytotic machinery, leading to a leaky glomerular filter. Pharmacological inhibition of p38 preserves nephrin surface expression and significantly attenuates albuminuria. Our data highlight the pivotal role of p38 in the genesis of diabetic proteinuria and the potential use of p38 inhibitors to slow down progression of kidney disease in patients with proteinuria.