Endothelial-Podocyte Crosstalk: The Missing Link Between Endothelial Dysfunction and Albuminuria in Diabetes

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, most people with diabetic nephropathy will never develop ESRD but will instead die of cardiovascular (CV) disease (CVD). The first evidence of kidney injury in diabetes is often microalbuminuria, itself also an independent risk marker for CVD. Although the two processes are closely associated, the recent failure of antialbuminuric therapies to affect CV outcomes has encouraged a reconsideration of how albuminuria may occur in diabetes and how increased urinary albumin excretion may be indicative of CV risk. The relationship between CVD and urinary albumin content (even within the normal range) is widely considered to reflect the common underlying pathology of endothelial dysfunction. At the same time, recent years have witnessed a growing appreciation that diabetic albuminuria commonly arises from damage to glomerular podocytes, specialized epithelial cells acting as the final barrier to macromolecular flow into the urinary filtrate. These superficially discordant paradigms can be assimilated by the emerging concept of endothelial-podocyte crosstalk across the glomerular filtration barrier, whereby the actions of one type of cell may profoundly influence the function of the other. The bidirectional nature of this paracrine network is illustrated by the actions of the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor-2 and activated protein C systems, among others. Identification of novel mediators of endothelial-podocyte crosstalk may lead to the development of more effective treatments for diabetic nephropathy and its sequelae.Even though it is the most common cause of end-stage renal disease (ESRD) worldwide, most people with diabetic nephropathy will never reach the stage of requiring dialysis or a kidney transplant but will instead die of cardiovascular (CV) disease (CVD). Often, the earliest indicator of kidney damage in diabetes is the abnormal passage of the protein albumin into the urinary filtrate, which is widely considered to reflect underlying endothelial dysfunction and is itself an independent predictor of CVD. Despite their well-recognized association, the manner in which endothelial dysfunction may result in albuminuria is incompletely understood. The passage of albumin into the urine is normally impeded by a three-layered glomerular filtration barrier composed of fenestrated glomerular endothelial cells lining the capillary loops, interdigitating podocytes lining the urinary space, and an interpositioned glomerular basement membrane (Fig. 1A–C). Recent evidence indicates that paracrine communication between the fenestrated endothelium and podocytes plays a critical role in maintaining filtration barrier integrity and that this communication may be disrupted by hyperglycemia and its associated hemodynamic and metabolic perturbations leading to albumin leakage. Here, we consider the roles of the superficially competing paradigms of endothelial dysfunction and podocyte injury in diabetic nephropathy and how these phenomena can be reconciled by the emerging concept of endothelial-podocyte crosstalk.Open in a separate windowFIG. 1.A: Scanning electron micrograph illustrating the fenestrated glomerular endothelium. B: Scanning electron micrograph illustrating interdigitating podocyte foot processes wrapped around the glomerular capillary wall. C: Transmission electron micrograph showing the structure of the glomerular filtration barrier composed of fenestrated endothelium, glomerular basement membrane, and interdigitating podocytes bridged by a molecular slit diaphragm. D: Transmission electron micrograph of the glomerular filtration barrier from a diabetic endothelial NO synthase–deficient mouse showing podocyte foot process effacement in the presence of normal glomerular endothelial fenestrations and ultrastructure.