Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy

Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury. As a calcium-dependent serine/threonine protein kinase involved in podocyte injury, protein kinase C isoform alpha (PKC alpha) was reported to regulate the phosphorylation of p66SHC. However, the role of PKC alpha/p66SHC in DN remains unknown. Klotho, an anti-aging protein with critical roles in protecting kidney, is expressed predominantly in the kidney and secreted in the blood. Nonetheless, the mechanism underlying amelioration of podocyte injury by Klotho in DN remains unclear. Our data showed that Klotho was decreased in STZ-treated mice and was further declined in diabetic KL +/- mice. As expected, Klotho deficiency aggravated diabetes-induced proteinuria and podocyte injury, accompanied by the activation of PKC alpha and p66SHC. In contrast, overexpression of Klotho partially ameliorated PKC alpha/p66SHC-mediated podocyte injury and proteinuria. In addition, in vitro experiments showed that activation of PKC alpha and subsequently increased intracellular reactive oxygen species (ROS) was involved in podocytic apoptosis induced by high glucose (HG), which could be partially reversed by Klotho. Hence, we conclude that Klotho might inhibit PKC alpha/p66SHC-mediated podocyte injury in diabetic nephropathy.