title: NLRP3 inflammasome mediates albumin-induced renal tubular injury through impaired mitochondrial function.
abstract: Proteinuria serves as a direct causative factor of renal tubular cell injury and is highly associated with the progression of chronic kidney disease via uncertain mechanisms. Recently, evidence demonstrated that both NLRP3 inflammasome and mitochondria are involved in the chronic kidney disease progression. The present study was undertaken to examine the role of NLRP3 inflammasome/mitochondria axis in albumin-induced renal tubular injury. In patients with proteinuria, NLRP3 was significantly up-regulated in tubular epithelial cells and was positively correlated with the severity of proteinuria. In agreement with these results, albumin remarkably activated NLRP3 inflammasome in both in vitro renal tubular cells and in vivo kidneys in parallel with significant epithelial cell phenotypic alteration and cell apoptosis. Genetic disruption of NLRP3 inflammasome remarkably attenuated albumin-induced cell apoptosis and phenotypic changes under both in vitro and in vivo conditions. In addition, albumin treatment resulted in a significant mitochondrial abnormality as evidenced by the impaired function and morphology, which was markedly reversed by invalidation of NLRP3/caspase-1 signaling pathway. Interestingly, protection of mitochondria function by Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP) or cyclosporin A (CsA) robustly attenuated albumin-induced injury in mouse proximal tubular cells. Collectively, these findings demonstrated a pathogenic role of NLRP3 inflammasome/caspase-1/mitochondria axis in mediating albumin-induced renal tubular injury. The discovery of this novel axis provides some potential targets for the treatment of proteinuria-associated renal injury.
authors: From the Department of Nephrology, Nanjing Children's Hospital and the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Yibo
authors: Y
authors: Zhuang
authors: From the Department of Nephrology, Nanjing Children's Hospital and.
authors: Guixia
authors: G
authors: Ding
authors: the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Min
authors: M
authors: Zhao
authors: the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Mi
authors: M
authors: Bai
authors: the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Lingyun
authors: L
authors: Yang
authors: the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Jiajia
authors: J
authors: Ni
authors: the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Rong
authors: R
authors: Wang
authors: From the Department of Nephrology, Nanjing Children's Hospital and the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Zhanjun
authors: Z
authors: Jia
authors: From the Department of Nephrology, Nanjing Children's Hospital and the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China.
authors: Songming
authors: S
authors: Huang
authors: From the Department of Nephrology, Nanjing Children's Hospital and the Institute of Pediatrics, Nanjing Medical University, Nanjing 210008, China zhaihua@njmu.edu.cn.
authors: Aihua
authors: A
authors: Zhang
mesh_terms: D000293:Adolescent; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008665:Metalloporphyrins / Q000494:pharmacology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012710:Serum Albumin, Bovine / Q000633:toxicity
chemical_list: D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D058847:Inflammasomes; D008665:Metalloporphyrins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D012710:Serum Albumin, Bovine; D016572:Cyclosporine; D020170:Caspase 1
keywords: Apoptosis; Epithelial Cell; Inflammasome; Kidney; Mitochondria; Mitochondrial Dysfunction; NLRP3 Inflammasome; Proteinuria; Renal Tubular Cells