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 NLRP3 inflammasome in mediating kidney injury. However, the role of NLRP3 in remnant kidney disease model is still undefined. The present study is 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, the 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 the TGF-β1 and the cellular phenotypic changes were detected. As expected, TGF-β1-induced alteration of PTC phenotype were abolished by NLRP3 siRNA in line with a protection of mitochondrial function. Taken together, NLRP3 deletion protected against renal fibrosis in 5/6 Nx disease model possibly via inhibiting mitochondrial dysfunction.
- Renal fibrosis
- NLRP3 inflammasome
- Mitochondrial oxidative stress
- Chronic kidney disease
- Copyright © 2015, American Journal of Physiology - Renal Physiology