BACKGROUND: We have previously reported that animals recovering from uranyl acetate (UA)-induced acute renal failure (ARF) were resistant to subsequent insult. Recent evidence suggests that apoptosis participates in tubular damage. We investigated the role of apoptosis in UA-induced ARF and attenuation of ARF in acquired resistance to UA in rats. METHODS: ARF was induced by an intravenous injection of UA (5 mg/kg) in rats. Rats of group 1 were injected with UA and followed for 28 days. Group 2 rats were injected with a second dose of UA (5 mg/kg) 14 days after the first injection and were followed for 14 days. All rats received an intraperitoneal injection of bromodeoxyuridine (BrdU) one hour before sacrifice. Using kidneys, histologic examination and immunohistochemical detection of proliferating cell nuclear antigen (PCNA), BrdU, Bcl-2, and Bax were performed. To detect apoptosis, electron microscopy, analysis of DNA fragmentation, and the TUNEL methods were adopted. RESULTS: UA increased the number of damaged renal tubules and serum creatinine, which peaked at 5 days in group 1, but both returned to baseline values by 14 days. Apoptosis was confirmed by electron microscopy and the "ladder" pattern of DNA fragments on gel electrophoresis. The number of apoptotic tubular cells evaluated by the TUNEL method showed two peaks at days 5 and 14 in group 1. The second peak of TUNEL-positive cells was preceded by an increased number of BrdU-positive nuclei, PCNA-positive nuclei, and total number of tubular epithelial cells. Renal damage after the second UA injection was markedly reduced. The peak number of apoptotic cells in group 2 was significantly less than that in group 1. CONCLUSIONS: Two peak levels of apoptotic cells occurred in UA-induced ARF. The first peak might play a role in UA-induced tubular damage, while the second one might represent the removal of excess regenerating cells during the recovery phase. Modulation of apoptotic cell death might be involved in the acquired resistance to rechallenge injury by UA.
BACKGROUND: We have previously reported that animals recovering from uranyl acetate (UA)-induced acute renal failure (ARF) were resistant to subsequent insult. Recent evidence suggests that apoptosis participates in tubular damage. We investigated the role of apoptosis in UA-induced ARF and attenuation of ARF in acquired resistance to UA in rats. METHODS:ARF was induced by an intravenous injection of UA (5 mg/kg) in rats. Rats of group 1 were injected with UA and followed for 28 days. Group 2 rats were injected with a second dose of UA (5 mg/kg) 14 days after the first injection and were followed for 14 days. All rats received an intraperitoneal injection of bromodeoxyuridine (BrdU) one hour before sacrifice. Using kidneys, histologic examination and immunohistochemical detection of proliferating cell nuclear antigen (PCNA), BrdU, Bcl-2, and Bax were performed. To detect apoptosis, electron microscopy, analysis of DNA fragmentation, and the TUNEL methods were adopted. RESULTS:UA increased the number of damaged renal tubules and serum creatinine, which peaked at 5 days in group 1, but both returned to baseline values by 14 days. Apoptosis was confirmed by electron microscopy and the "ladder" pattern of DNA fragments on gel electrophoresis. The number of apoptotic tubular cells evaluated by the TUNEL method showed two peaks at days 5 and 14 in group 1. The second peak of TUNEL-positive cells was preceded by an increased number of BrdU-positive nuclei, PCNA-positive nuclei, and total number of tubular epithelial cells. Renal damage after the second UA injection was markedly reduced. The peak number of apoptotic cells in group 2 was significantly less than that in group 1. CONCLUSIONS: Two peak levels of apoptotic cells occurred in UA-induced ARF. The first peak might play a role in UA-induced tubular damage, while the second one might represent the removal of excess regenerating cells during the recovery phase. Modulation of apoptotic cell death might be involved in the acquired resistance to rechallenge injury by UA.