Tubular and Interstitial Cell Apoptosis in the Streptozotocin-Diabetic Rat Kidney

Abstract

Background/Aims: Angiotensin II (Ang II) mediates progressive nephron loss in diabetes and stimulates apoptotic cell death in several tissues. We studied the extent of apoptosis in streptozotocin (STZ) induced diabetic nephropathy in the rat and the effects of insulin and type 1 (AT₁) or type 2 (AT₂) Ang II receptor blockade with losartan or PD123319, respectively. Methods: Three groups of rats were studied after 2 and 12 weeks: (1) controls ; (2) STZ-diabetic rats (STZ rats), and (3) STZ-diabetic rats with insulin implants. Additional rats were treated with losartan (25 mg/kg/day) and/or PD123319 (10 mg/kg/day) for 2 weeks. Kidneys were examined for apoptosis, using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, DNA laddering, and electron microscopy. Immunoblotting determined expression of the proapoptotic protein Bax and of the antiapoptotic protein Bcl-2 in proximal tubules. Results: Diabetes caused a significant increase in apoptosis, involving tubular and interstitial cells of cortex and medulla, but not glomerular cells (2 weeks: controls 264 ± 94 vs. STZ rats 1,501 ± 471 apoptotic nuclei/kidney section; p < 0.02; n = 6–8), an effect reversed by insulin. In STZ rats, ultrastructural examination revealed chromatin condensation and nuclear fragmentation in tubular and interstitial cells. At 2 and 12 weeks, a significant decrease in the expression of the antiapoptotic protein Bcl-2 occurred in STZ rat proximal tubules, with restoration by insulin. In STZ rats, treatment for 2 weeks with losartan or PD123319 inhibited apoptosis in the kidneys, with no additive effect of the combination therapy. Conclusions: Apoptosis occurs in diabetic nephropathy, involving tubular and interstitial cells, an effect reversed by insulin therapy. Furthermore, the effects of AT₁ or AT₂ receptor blockade suggest that Ang II is involved in mediating apoptosis in the diabetic kidney.

The effects of grape seed on apoptosis-related gene expression and oxidative stress in streptozotocin-induced diabetic rats

“…26 Kumar et al have shown that apoptotic cell death plays a role in the occurrence of kidney damage in diabetic nephropathy. 27 Wong et al reported that elevated blood glucose levels affect apoptosis-controlling genes. 28 We found that CASP1, IL1-alpha, BAD, DFFA, DFFB, CASP6 and DIABLO gene expression changes were significantly increased in diabetic rats compared to control rats.…”

From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease

“…Evidence for a primary role of apoptosis in either human or experimental diabetic nephropathy is scant (51)(52)(53)(54). However, podocyte apoptosis can be demonstrated in cell culture.…”

Antidiabetic effect of combined spices ofAllium sativum,Zingiber officinaleandCapsicum frutescensin alloxan-induced diabetic rats

“…Long-term damage, dysfunction and failure of the kidneys are major complications of diabetes mellitus. Increased glucose levels in the blood have been shown to lead to oxidative stress, which is considered as one of the causative factors of diabetes-associated kidney disorders such as apoptosis, tubular atrophy and necrosis (Kumar et al 2004;El-Midaoui & de Champlain 2005). Administration of the GGCP extract or glibenclamide improved the architecture of the kidney and by extension restored its functionality.…”