Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?

Abstract

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease in the United States and is a major cause of cardiovascular disease and death. DN develops insidiously over a span of years before clinical manifestations, including microalbuminuria and declining glomerular filtration rate (GFR), are evident. During the clinically silent period, structural lesions develop, including glomerular basement membrane (GBM) thickening, mesangial expansion, and glomerulosclerosis. Once microalbuminuria is clinically apparent, structural lesions are often considerably advanced, and GFR decline may then proceed rapidly toward end-stage kidney disease. Given the current lack of sensitive biomarkers for detecting early DN, a shift in focus toward examining the cellular and molecular basis for the earliest structural change in DN, i.e., GBM thickening, may be warranted. Observed within one to two years following the onset of diabetes, GBM thickening precedes clinically evident albuminuria. In the mature glomerulus, the podocyte is likely key in modifying the GBM, synthesizing and assembling matrix components, both in physiological and pathological states. Podocytes also secrete matrix metalloproteinases, crucial mediators in extracellular matrix turnover. Studies have shown that the critical podocyte-GBM interface is disrupted in the diabetic milieu. Just as healthy podocytes are essential for maintaining the normal GBM structure and function, injured podocytes likely have a fundamental role in upsetting the balance between the GBM's synthetic and degradative pathways. This article will explore the biological significance of GBM thickening in DN by reviewing what is known about the GBM's formation, its maintenance during health, and its disruption in DN.

Keywords: glomerular filtration barrier; podocyte; podocyte- glomerular basement membrane interface.

Fig. 1.

Ultrastrnctural images of the glomerular filtration barrier (GFB), normal vs. diabetic. A: electron micrograph of the normal GFB at maturity. The micrograph shows the capillary lumen supported by the fenestrated endothelium, glomerular basement membrane (GBM) proper, and interdigitating foot processes of the visceral glomerular epithelial cells or “podocytes.” B: electron micrograph of the diseased GFB in diabetes mellitus. There is a thickened GBM due to marked widening of the lamina densa, with prominent podocyte foot process effacement. Expansion of the mesangial matrix is also present.

Fig. 2.

Schematic representation of the critical podocyte-GBM interface. The podocyte-GBM interface forms a signaling platform that controls many cell fate decisions. The GBM matrix is composed of networks of laminin-α₅β₂γ₁, α₃α₄α₅(IV)-collagen, nidogens, and heparan sulfate proteoglycans, including agrin and perlecan. The key cell-matrix adhesion receptor is integrin-α₃β₁, which connects laminin-α₅β₂γ₁ in the GBM, via various adaptor proteins, to the intracellular actin cytoskeleton. Tetraspanin CD151 strongly binds to integrin-α₃β₁, promoting strong linkage of podocytes to the GBM. Podocytes also express other cell-matrix adhesion receptors that modulate podocyte adhesion to the GBM, including integrin-α_vβ₃, dystroglycan, syndecan-1, and syndecan-4. Cell-matrix adhesion receptors on the endothelial surface of the GBM include syndecan-1, syndecan-4, integrin-α_vβ₃, and integrin-α_vβ₅.