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Background: Crescentic glomerulonephritis is a rapidly progressive form of nephritis and is usually resistant to therapeutic intervention. Apoptosis plays a role in the resolution of glomerulonephritis. We investigated the effects of local kidney irradiation on the progression of experimental crescentic glomerulonephritis., Methods: The following three experimental rat groups were generated: (1) Group I, sham-operated control (n = 12); (2) Group II, rats injected intravenously with rabbit anti-rat GBM antibody (nephrotoxic serum, NTS) (n = 23), and (3) Group III, a single low-dose irradiation of 0.5 Gy X-ray to both kidneys at days 6, 13, 20, and 27 after NTS injection (n = 55). Renal function and blood leukocyte count were examined in different groups of rats at various time points. Kidneys obtained at various time points were analyzed to determine the effects of radiation in experimental nephritis., Results: Radiation of the kidneys reduced the levels of blood urea nitrogen and serum creatinine compared with Group II nephritic rats of similar age (p < 0.05 or 0.001). No apparent changes in blood leukocyte counts were noted in various experimental groups. Glomerular hypercellularity, crescents, global sclerosis and tubulointerstitial damage developed gradually in Group II rats, but were decreased (p < 0.05 or 0.001) after radiation treatment. The extent of tubulointerstitial damage was also reduced, and radiation-associated histological improvements were accompanied by reduced infiltration of macrophages in the glomeruli and interstitium. The numbers of PCNA- and ED1-positive cells were reduced in the kidneys at 1 day post-irradiation, of rats irradiated at 6 and 13 days after NTS injection, compared with Group II at similar time intervals (p < 0.05). A larger numbers of TUNEL-positive cells were noted at 1 day post-irradiation in rats irradiated at 6 and 13 days after NTS injection, compared with Group II at similar time intervals (p < 0.05). Immunostaining for macrophages ED1 and TUNEL staining of serial sections of irradiated nephritic kidneys showed few ED1-positive macrophages stained for TUNEL. Overexpression of active caspases 3 and 7 was noted in irradiated kidneys, compared with the corresponding Group II rats at similar time intervals. Western blot analysis showed marked increase in active caspase 3 and active caspase 7 expression in irradiated kidneys compared with NTS injection only. A marked increase in the expression of p53 protein, which is closely related to radiation-induced apoptosis, was also observed in irradiated kidneys compared with NTS injection only., Conclusion: Our study showed that renal radiation can alter acute glomerular inflammation by inducing apoptosis of intrinsic and infiltrating cells in the kidney in a rat model of crescentic glomerulonephritis. Low-dose kidney irradiation can inhibit the progression of experimental nephritis through inducing apoptosis., (Copyright 2008 S. Karger AG, Basel)

Aim: The aim of this study was to determine the effects of kidney pathology on overall survival and longevity and the combined effects of chronic suppression of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) activity and lifelong caloric restriction on age-associated nephropathy., Methods: We analyzed the kidneys of rats with suppressed GH activity through genetic manipulation with an antisense GH transgene. Rats were fed normally or with a 30% calorie-restricted diet for 24-26 months. The kidneys of male wild-type young (6 months) and old (24-26 months) rats were compared with male hemizygote transgenic young (6 months) and old (24-26 months) rats fed with either regular diet or 30% calorie-restricted diet for their entire life span., Results: The transgenic rats had relatively less pituitary GH-secreting cells, and the plasma levels of IGF-1 were decreased by 53% in homozygote rats (tg/tg) and by 28% in hemizygote rats (tg/wt) compared to wild-type rats (wt/wt) of the same age (6 months). Wild-type rats fed the regular diet developed age-associated nephropathy as they aged, showing severe inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis. In addition, about 83% of the wild-type rats allowed to survive naturally showed signs of nephropathy. In contrast, only 26% of the naturally surviving hemizygote rats showed features of nephropathy, despite the fact that these rats lived 8% longer (maximum survival 171 weeks) than the wild-type rats (maximum survival 158 weeks). When chronic suppression of GH/IGF-1 activity was combined with lifelong caloric restriction, however, age- associated nephropathy was nonexistent in hemizygote transgenic rats, and they showed about 30% increase in survival (maximum survival 204 weeks). There was no significant difference in the rate of neoplastic or nonneoplastic lesions (other than in the kidney) in the regularly fed wild-type rats or in the calorie-restricted hemizygote transgenic rats that survived longer., Conclusion: We concluded that kidney pathology is an important determinant of overall survival, and that prevention of kidney pathology by dietary restriction, combined with chronic suppression of GH/IGF-1 activity, significantly extends overall survival and longevity., (Copyright 2008 S. Karger AG, Basel.)

Cisplatin (cis-diamminedichloroplatinum(II)) is an effective chemotherapeutic agent, and is successfully used in the treatment of a wide range of tumors. Despite its effectiveness as an anti-tumor drug, nephrotoxic side effects have significantly restricted its clinical use. Tubular epithelial cell deletion following cisplatin treatment is a major cause of renal injury. Oxidative stress significantly contributes to cisplatin-associated cytotoxicity, and use of antioxidants could counteract such cytotoxic effects of cisplatin. The renal microenvironmental changes following cisplatin treatment is a complex process and could be broadly categorized into three main pathological events, which at times might overlap: initial cytotoxic events, inflammatory events and fibroproliferative events. Stress responses and heat shock proteins generated following cisplatin treatment are actively involved in the initiation and progression of these events. In this article, we will briefly summarize factors involved in various phases of cisplatin-induced renal injuries.