Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus: role in the development of diabetic glomerular disease.

AIMS/HYPOTHESIS: Podocyte loss by apoptosis, in addition to favouring progression of established diabetic nephropathy, has been recently indicated as an early phenomenon triggering the initiation of glomerular lesions. This study aimed to assess the rate of glomerular cell death and its relationship with renal functional, structural and molecular changes in rats with experimental diabetes.

METHODS: Male Sprague-Dawley rats with streptozotocin-induced diabetes and coeval non-diabetic control animals were killed at 7 days and at 2, 4 and 6 months for the assessment of apoptosis, renal function, renal structure and the expression of podocyte markers and apoptosis- and cell cycle-related proteins.

RESULTS: Glomerular cell apoptosis was significantly increased in diabetic vs non-diabetic rats at 4 months and to an even greater extent at 6 months, with podocytes accounting for 70% of apoptosing cells. The increase in apoptosis was preceded by increases in proteinuria, albuminuria and mean glomerular and mesangial areas, and by reductions in glomerular cell density and content of synaptopodin and Wilms' tumour protein-1. It coincided with the development of mesangial expansion and glomerular sclerosis, and with the upregulation/activation both of tumour protein p53, which increased progressively throughout the study, and of p21 (also known as cyclin-dependent kinase inhibitor 1A, CIP1 and WAF1), which peaked at 4 months and decreased thereafter.

CONCLUSIONS/INTERPRETATION: Glomerular cell (podocyte) apoptosis is not an early feature in the course of experimental diabetic glomerulopathy, since it is preceded by glomerular hypertrophy, which may decrease glomerular cell density to the point of inducing compensatory podocyte hypertrophy. This is associated with reduced podocyte protein expression (podocytopathy) and proteinuria, and ultimately results in apoptotic cell loss (podocytopenia), driving progression to mesangial expansion and glomerular sclerosis.