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Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1

Authors: Nai-jun Miao1, Hong-yan Xie1, Dan Xu1, Jian-yong Yin2, Yan-zhe Wang3, Bao Wang1, Fan Yin1, Zhuan-li Zhou1, Qian Cheng1, Pan-pan Chen1, Li Zhou1, Hong Xue1, Wei Zhang1, Xiao-xia Wang2, Jun Liu1, Li-min Lu1
1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
2 Department of Nephrology, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
3 Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200032, China
DOI: 10.1038/s41401-018-0177-5
Received: 14 June 2018
Accepted: 24 September 2018
Advance online: 31 October 2018

Abstract

Caspase-11 is a key upstream modulator for activation of inflammatory response under pathological conditions. In this study, we investigated the roles of caspase-11 in the maturation of interleukin-1β (IL-1β) and development of renal interstitial fibrosis in vivo and in vitro. Mice were subjected to unilateral ureteral obstruction (UUO). The mice were treated with either caspase-11 inhibitor wedelolactone (Wed, 30 mg/kg/day, ig) for 7 days or caspase-11 siRNA (10 nmol/20 g body weight per day, iv) for 14 days. The mice were euthanized on day 14, their renal tissue and blood sample were collected. We found that the obstructed kidney had significantly higher caspase-11 levels and obvious tubular injury and interstitial fibrosis. Treatment with Wed or caspase-11 siRNA significantly mitigated renal fibrosis in UUO mice, evidenced by the improved histological changes. Furthermore, caspase-11 inhibition significantly blunted caspase-1 activation, IL-1β maturation, transforming growth factor-β (TGF-β), fibronectin, and collagen I expressions in the obstructed kidney. Renal tubular epithelial NRK-52E cells were treated in vitro with angiotensin (Ang, 1 μmol/L), which stimulated caspase-11 activation and IL-1β maturation. Treatment with IL-1β (20 ng/ml) significantly increased the expression of TGF-β, fibronectin, and collagen I in the cells. Ang II-induced expression of TGF-β, fibronectin, and collagen I were suppressed by caspase-11 siRNA or Wed. Finally, we revealed using co-immunoprecipitation that caspase-11 was able to interact with caspase-1 in NRK-52E cells. These results suggest that caspase-11 is involved in UUO-induced renal fibrosis. Elevation of caspase-11 in the obstructed kidney promotes renal fibrosis by stimulating caspase-1 activation and IL-1β maturation.
Keywords: caspase-11; interleukin-1β; angiotensin II; unilateral ureteral obstruction; renal fibrosis

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