The impact of Caspase-1 deletion on apoptosis and acute kidney injury in a murine transplant model |
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| Affiliation: | 1. Dept. of Surgery, Colorado Center for Transplantation Care, Research and Education, University of Colorado Denver, Aurora, CO, United States;2. Dept. of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, CO, United States;3. Dept. of Immunology and Microbiology, University of Colorado Denver, Aurora, CO, United States;4. Division of Pulmonary, Critical Care & Sleep Medicine, University Florida, Gainesville, FL, United States;5. Dept. of Pediatrics, Division of Cardiology, University of Colorado Denver, Aurora, CO, United States;6. Div. of Pediatric Cardiology, University of Florida, Gainesville, FL, United States;1. Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA;2. Department of Microbiology and Immunology, University of Colorado, Aurora, CO, USA;3. Department of Surgery, University of Colorado, Aurora, CO, USA;4. Division of Pulmonary Diseases, Section of Advanced Lung Disease and Lung Transplantation, Baylor University Medical Center, Dallas, TX, USA;1. Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China;2. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China;3. Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou Medical University, Xuzhou, Jiangsu, China;4. The Third People''s Hospital of Bengbu, Bengbu, Anhui, China;5. Department of Medicine, Hospital of the University of Pennsylvania;6. Xuzhou Children’s Hospital, Xuzhou, Jiangsu, China |
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| Abstract: | BackgroundCaspase-1 knockout mice (Casp1KO) are protected from Acute Kidney Injury (AKI) after warm ischemia/reperfusion injury in non-transplant models. Since Caspase-1 plays a central role as an inflammatory response initiator, we hypothesized that Casp1KO mice would be protected from AKI following transplant.MethodsRenal tubular cells (RTECs) were subjected to cold storage and rewarming (CS/REW). C57Bl/6 J wild type or Casp1KO kidneys were subjected to CI for 30 min and then transplanted into wild type recipients (CI + Txp). The recipients underwent bilateral native nephrectomy at the time of transplant. Serum creatinine (sCr) was measured 24 h after native nephrectomy to assess transplant function.ResultsWe found that RTECs subjected to CS/REW had significantly increased expression of the Caspase-1 and inflammasome protein NLRP1. Wild type kidneys subjected to CI + Txp into wild type recipients also demonstrated significantly increased Caspase-1 and NLRP1 protein expression compared to kidneys transplanted from Casp1KO donors into wild type recipients. Caspase-1 deletion results in significantly decreased RTEC apoptosis in transplanted Casp1KO vs WT kidneys. Surprisingly, however, renal function, ATN scores including brush border injury, cast formation and tubular simplification were similar in both groups and not significantly different.ConclusionsOur data suggest that other triggers of inflammation and programmed necrosis may need to be inhibited in addition to attenuating Caspase-1 to fully prevent AKI after kidney transplant. Importantly, requirements may be distinct for AKI induced by transplantation as opposed to other transient models such as the clamp model of AKI. |
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