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.

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

“…In the present study, supplementation with Asp improved renal oxidative stress and structures of ESL in diabetic mice. The reduction in the rate of foot process effacement with the amelioration of ESL might be related to the reduction in GBM thickening, because injured podocytes contribute to the perturbation of the balance between the synthetic and degradative pathways of GBM [37]. However, the circulating concentrations of Asp and Citrulline did not change between the DKD and Tx groups.…”

The nature and biology of basement membranes

“…Diabetic nephropathy is the leading cause of chronic kidney disease in the U.S. and is often seen in combination with cardiovascular disease. The basis for the BM thickening, which precedes proteinuria, is not well understood or studied, but may involve changes in synthesis, degradation/remodeling, and/or glycation and that may be a response to podocyte injury [89]. …”

Epithelial and endothelial mesenchymal transition and their role in diabetic kidney disease

“…During the clinically silent stage, structural lesions include glomerular basement membrane thickening build up and extreme deposition of extracellular matrix (ECM) in the glomerulus and interstitial area. It, finally, leads to glomerulosclerosis and tubulointerstitial fibrosis as well (2,3). Pathophysiology of diabetic nephropathy (DN) has intensively been studied.…”