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

Abstract

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 streptozotocininduced 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.

Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes

“…Although the reason is unclear, one possible explanation is that podocyte apoptosis may be abrogated by the inhibition of the foregoing event, podocyte hypertrophy. Menini et al [45] demonstrated that podocyte apoptosis is not an early feature of experimental DN, as it is preceded by glomerular hypertrophy. In addition, Advani et al [46] found that inhibiting glomerular hypertrophy with an EGF receptor blocker preserves podocyte number in DM glomeruli.…”

Sirtuin 1: A Target for Kidney Diseases

“…In vitro study showed that high glucose-induced apoptosis in podocytes was mediated by p53 pathways (52). In vivo study showed that advanced oxidation protein products induced by diabetes led to podocyte apoptosis by a p53 apoptotic pathway, which was preceded by the increase in albuminuria (53). P53 was upregulated and activated in the renal cortex of db/db mice and streptozotocin (STZ)-induced diabetic mice and rats, leading to the increased podocyte apoptosis and albuminuria (53,54).…”

“…In vivo study showed that advanced oxidation protein products induced by diabetes led to podocyte apoptosis by a p53 apoptotic pathway, which was preceded by the increase in albuminuria (53). P53 was upregulated and activated in the renal cortex of db/db mice and streptozotocin (STZ)-induced diabetic mice and rats, leading to the increased podocyte apoptosis and albuminuria (53,54). In addition, p53 could also increase the apoptosis of mesangial cells and tubular cells, resulting in the aggravation of kidney damage (43,54,55).…”

“…In addition, p53 could also increase the apoptosis of mesangial cells and tubular cells, resulting in the aggravation of kidney damage (43,54,55). Furthermore, deletion of the p53 gene or inhibition of p53 protein function by its inhibitor conferred a protective phenotype because of the reduced apoptosis of renal cells (53,54). SIRT1 bound and deacetylated the C-terminal Lys382 of p53, which destabilized the p53 protein and reduced its transcriptional activity, resulting in the decrease of apoptosis (15,56,57).…”

Minocycline Attenuates Kidney Injury in a Rat Model of Streptozotocin-Induced Diabetic Nephropathy

“…7) Podocyte loss resulting from apoptosis has played an important role in the onset of albuminuria and the pathogenesis of DN. 8) Recent studies demonstrate that preventing podocyte apoptosis may ameliorate renal injury and decrease proteinuria in DN. 9,10) Recent studies have shown that anti-inflammatory and immunomodulatory actions of minocycline are not related to its antimicrobial property.…”