Role of the podocyte signal-transduction systems in the pathogenesis of diabetic nephropathy

Abstract

Diabetic nephropathy, which develops in 30–40% of diabetic patients, is a leading cause of end-stage renal disease (ESRD), accounting for more than 40% of new ESRD cases undergoing treatment in the USA and other developed countries [1, 2]. In its initial stage, diabetic patients excrete macromolecules such as albumin, indicating an abnormality in the glomerular permeability barrier, followed by a gradual decline of GFR with the appearance of overt proteinuria [3]. The glomerular permeability barrier consists of endothelial cells, the glomerular basement membrane, and podocytes. Podocytes are highly specialized epithelial cells with interdigitating foot processes that participate in the prevention of proteinuria [4]. In the early stage of diabetic nephropathy, effacement of the foot processes is observed in podocytes, resulting in the leakage of macromolecules, including albumin, into the urine [4]. Loss of trace amounts of albumin in the urine, microalbuminuria, has been regarded as an early marker of diabetic nephropathy, although microalbuminuria is also observed in patients with metabolic syndrome, indicating that insulin resistance may cause podocyte injury [5]. To examine the role of podocyte insulin signaling in the pathogenesis of diabetic nephropathy, Welsh et al. [6] recently analyzed mice with podocyte-specific deletion of the insulin receptor. They showed that these mice developed significant proteinuria by 5 weeks of age; histological glomerular changes resembling those of diabetic nephropathy, for example effacement of podocyte foot processes, thickening of the basement membrane, accumulation of mesangial matrix, and glomerulosclerosis in a normoglycemic environment, were also observed. In in-vivo and invitro analysis of podocytes lacking the insulin receptor, both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Akt pathways, the two major pathways downstream of the insulin receptor, were shown to be abrogated. It was also reported that insulin-induced reorganization of actin cytoskeleton in podocytes, which, in investigations of familial nephritic syndromes, was revealed to be important in the maintenance of the glomerular permeability barrier [7], was affected by the absence of the insulin receptor. These findings suggested that impaired insulin signaling in podocytes is sufficient for development of some pathological features of diabetic nephropathy, although its molecular mechanism was not fully investigated. In addition, in these mice, the role of other insulin-regulated pathways important for the maintenance of podocyte function, such as autophagy and mammalian target of rapamycin (mTOR) pathways were not evaluated [8, 9].