Caspase-12 and Diabetic Nephropathy

Abstract

Since the seminal observation that high glucose induces renal cell apoptosis in culture and in vivo ,1 investigators have sought to identify the molecular mechanisms of renal cell apoptosis in diabetic nephropathy. In this issue of JASN , Brezniceanu et al. 2 explore proapoptotic genes that are upregulated differentially by reactive oxygen species (ROS) in renal proximal tubular cells of diabetic (db/db) mice. Expression of caspase-12 and other endoplasmic reticulum (ER) stress genes, such as HSPA5/GRP78/BiP and CHOP, are increased in the proximal tubules of these mice compared with nondiabetic and diabetic catalase transgenic mice. Reduction of ROS generation also inhibits albumin-stimulated expression and activity of caspase-12 in a human proximal tubule cell line (HK-2). Furthermore, knockdown of caspase-12 with small interfering RNAs reduces albumin-induced apoptosis in HK-2 cells. The authors of this article conclude that albuminuria may induce ROS-mediated ER stress and subsequent tubular apoptosis in diabetic kidneys. The involvement of caspase-12 in this process, especially in human cells, stands out as the most original part of the article; however, no information is provided on human diabetic nephropathy, and the key question is how relevant these data are to humans. There is increasing evidence that renal cells, including tubular cells, are lost through apoptosis in experimental and human diabetic nephropathy. Recent efforts to identify novel changes …