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Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1
- Source :
- Acta Pharmacol Sin
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group UK, 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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Interleukin-1beta
Caspase 1
urologic and male genital diseases
Kidney
Article
03 medical and health sciences
0302 clinical medicine
In vivo
Coumarins
Internal medicine
Renin–angiotensin system
medicine
Renal fibrosis
Animals
Pharmacology (medical)
Gene Silencing
RNA, Small Interfering
Pharmacology
biology
business.industry
Angiotensin II
General Medicine
Caspase Inhibitors
Fibrosis
Caspases, Initiator
Extracellular Matrix
Rats
Fibronectin
Enzyme Activation
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Caspases
biology.protein
Kidney Diseases
business
Transforming growth factor
Ureteral Obstruction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Acta Pharmacol Sin
- Accession number :
- edsair.doi.dedup.....9a7ce0157ebc3bb802655e866a48c363