Podocyte Depletion Causes Glomerulosclerosis

TLDR

Glomerular injury and proteinuria in diabetes and IgA nephropathy are linked to podocyte depletion, and rodents lack a diphtheria toxin receptor, rendering them resistant to DT. The study developed a transgenic rat expressing human diphtheria toxin receptor specifically in podocytes to investigate the causal link between podocyte depletion and glomerulosclerosis. A transgenic rat expressing human diphtheria toxin receptor specifically in podocytes was created to allow controlled podocyte depletion via DT injection. DT injection in transgenic rats caused dose‑dependent podocyte depletion, producing three injury stages—mesangial expansion with transient proteinuria, progressive sclerosis with mild proteinuria, and severe sclerosis with high proteinuria and reduced function—mirroring human disease and supporting podocyte loss as a key driver of glomerulosclerosis.

Abstract

Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.