title: NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy.
abstract: Progressive fibrosis in chronic kidney disease (CKD) is the well-recognized cause leading to the progressive loss of renal function. Emerging evidence indicated a pathogenic role of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in mediating kidney injury. However, the role of NLRP3 in the remnant kidney disease model is still undefined. The present study was undertaken to evaluate the function of NLRP3 in modulating renal fibrosis in a CKD model of 5/6 nephrectomy (5/6 Nx) and the potential involvement of mitochondrial dysfunction in the pathogenesis. Employing NLRP3(+/+) and NLRP3(-/-) mice with or without 5/6 Nx, we examined renal fibrotic response and mitochondrial function. Strikingly, tubulointerstitial fibrosis was remarkably attenuated in NLRP3(-/-) mice as evidenced by the blockade of extracellular matrix deposition. Meanwhile, renal tubular cells in NLRP3(-/-) mice maintained better mitochondrial morphology and higher mitochondrial DNA copy number, indicating an amelioration of mitochondrial abnormality. Moreover, NLRP3 deletion also blunted the severity of proteinuria and CKD-related hypertension. To further evaluate the direct role of NLRP3 in triggering fibrogenesis, mouse proximal tubular cells (PTCs) were subjected to transforming growth factor β1 (TGF-β1), and the cellular phenotypic changes were detected. As expected, TGF-β1-induced alterations of PTC phenotype were abolished by NLRP3 small interfering RNA, in line with a protection of mitochondrial function. Taken together, NLRP3 deletion protected against renal fibrosis in the 5/6 Nx disease model, possibly via inhibiting mitochondrial dysfunction.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing 210008; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029; and Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing 210008; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029; and Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Song
authors.initials: S
authors.lastname: Mao
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing 210008; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029; and Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing 210008; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029; and Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing 210008; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029; and Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing 210008; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029; and Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing 210008; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029; and Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China zhaihua@njmu.edu.cn.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006973:Hypertension / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D028361:Mitochondrial Diseases / Q000150:complications*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D009392:Nephrectomy; D009400:Nephrosclerosis / Q000209:etiology* / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology; D034741:RNA, Small Interfering; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D016212:Transforming Growth Factor beta
chemical_list: D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta
keywords: NLRP3 inflammasome; chronic kidney disease; mitochondrial dysfunction