NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy

Am J Physiol Renal Physiol. 2016 May 15;310(10):F1081-8. doi: 10.1152/ajprenal.00534.2015. Epub 2016 Feb 17.

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.

Keywords: NLRP3 inflammasome; chronic kidney disease; mitochondrial dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Hypertension / etiology
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Diseases / complications*
  • NLR Family, Pyrin Domain-Containing 3 Protein / physiology*
  • Nephrectomy
  • Nephrosclerosis / etiology*
  • Nephrosclerosis / metabolism
  • Proteinuria / etiology
  • RNA, Small Interfering
  • Renal Insufficiency, Chronic / complications*
  • Transforming Growth Factor beta

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA, Small Interfering
  • Transforming Growth Factor beta