Diabetic Kidney Disease, Endothelial Damage, and Podocyte-Endothelial Crosstalk

Abstract

Diabetes-related complications are a significant source of morbidity and mortality worldwide. Diabetic kidney disease is a frequent microvascular complication and a primary cause of kidney failure in patients with diabetes. The glomerular filtration barrier is composed of 3 layers: the endothelium, glomerular basement membrane, and podocytes. Podocytes and the endothelium communicate through molecular crosstalk to maintain filtration at the glomerular filtration barrier. Chronic hyperglycemia affects all 3 layers of the glomerular filtration barrier, as well as the molecular crosstalk that occurs between the 2 cellular layers. One of the earliest events following chronic hyperglycemia is endothelial cell dysfunction. Early endothelial damage is associated with progression of diabetic kidney disease. However, current therapies are based in controlling glycemia and arterial blood pressure without targeting endothelial dysfunction. Disruption of the endothelial cell layer also alters the molecular crosstalk that occurs between the endothelium and podocytes. This review discusses both the physiologic and pathologic communication that occurs at the glomerular filtration barrier. It examines how these signaling components contribute to podocyte foot effacement, podocyte detachment, and the progression of diabetic kidney disease.

Keywords: Podocyte-endothelial crosstalk; albuminuria; diabetic kidney disease; diabetic nephropathy; microvascular.

Figure 1

Endothelial-podocyte crosstalk. (A) Transmission electron micrograph of a normal mouse glomerular filtration barrier shows podocyte (P) foot process, glomerular basement membrane (GBM), and endothelial cells (EC; scale bar: 500 nm). (B) Under physiologic conditions (left), various secreted factors are exchanged between podocytes and endothelial cells to allow for maintenance of the glomerular filtration barrier. During diabetic nephropathy (right), increased reactive oxygen species (ROS) production can lead to thinning of the glycocalyx of the endothelium, as well as cellular damage to both endothelial cells and podocytes. Overactivation of several pathways leads to endothelial dysfunction, podocyte foot effacement, and eventually podocyte detachment. Abbreviations: eNOS, endothelial nitric oxide synthase; ET_AR, endothelin A receptor; TGFβ, transforming growth factor β; TRPC6, transient receptor potential canonical 6.