Renal atrophy after ischemia–reperfusion injury depends on massive tubular apoptosis induced by TNFα in the later phase
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Recent studies have suggested that acute kidney injury (AKI) develops into chronic kidney disease (CKD). However, a mechanism for disease progression from AKI to CKD has not been established. We developed two ischemia–reperfusion injury (IRI) mouse models, a repaired kidney model and an atrophic kidney model, and studied the mechanisms of renal atrophy after IRI by comparing the two models. We found that renal atrophy after IRI depended on tubular apoptosis at 14 days after IRI. Moreover, we found that Tnfα and FasL mRNA were synchronously expressed at the time of tubular apoptosis. To elucidate the relationship between tubular apoptosis and apoptotic ligands, we administered TNFα and FasL neutralizing antibodies according to the time of tubular apoptosis. TNFα blockade significantly repressed tubular apoptosis, resulting in the prevention of renal atrophy. FasL blockade could not repress tubular apoptosis, resulting in renal atrophy. We also found that TNF receptors were expressed in the kidney at 14 days after IRI, but Fas receptor was not. We concluded that renal atrophy after IRI depends on tubular apoptosis induced by the TNFα signaling pathway in the later phase of renal IRI, and that TNFα blockade could be a potential new therapeutic approach for improving renal prognosis after AKI.
KeywordsTNFα Apoptosis Atrophy Ischemia–reperfusion injury
This work was supported by a Grant-in-Aid for Scientific Research (C, 23591197) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Conflict of interest
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