期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/ijms22010271
关键词
cyclophilin; acute kidney injury; cell death; chronic kidney disease; inflammation; macrophage; neutrophil; renal fibrosis
资金
- National Health and Medical Research Council of Australia [1058175]
- Gilead Sciences
- Australian Postgraduate Award
- National Health and Medical Research Council of Australia [1058175] Funding Source: NHMRC
The study demonstrated that the selective cyclophilin inhibitor GS-642362 effectively protected against acute kidney injury and renal fibrosis in mouse models. The treatment reduced cell death, inflammatory cell infiltration, and fibrosis, supporting further investigation of cyclophilin blockade in various kidney diseases.
Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.
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