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Article

Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

1
Monash Medical Centre, Department of Nephrology, Clayton, VIC 3168, Australia
2
Centre for Inflammatory Diseases, Monash University, Clayton, VIC 3168, Australia
3
Gilead Sciences, Foster City, CA 94404, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Int. J. Mol. Sci. 2021, 22(1), 271; https://doi.org/10.3390/ijms22010271
Received: 28 October 2020 / Revised: 22 December 2020 / Accepted: 22 December 2020 / Published: 29 December 2020
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. View Full-Text
Keywords: cyclophilin; acute kidney injury; cell death; chronic kidney disease; inflammation; macrophage; neutrophil; renal fibrosis cyclophilin; acute kidney injury; cell death; chronic kidney disease; inflammation; macrophage; neutrophil; renal fibrosis
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MDPI and ACS Style

Leong, K.G.; Ozols, E.; Kanellis, J.; Badal, S.S.; Liles, J.T.; Nikolic-Paterson, D.J.; Ma, F.Y. Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis. Int. J. Mol. Sci. 2021, 22, 271. https://doi.org/10.3390/ijms22010271

AMA Style

Leong KG, Ozols E, Kanellis J, Badal SS, Liles JT, Nikolic-Paterson DJ, Ma FY. Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis. International Journal of Molecular Sciences. 2021; 22(1):271. https://doi.org/10.3390/ijms22010271

Chicago/Turabian Style

Leong, Khai Gene, Elyce Ozols, John Kanellis, Shawn S. Badal, John T. Liles, David J. Nikolic-Paterson, and Frank Y. Ma. 2021. "Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis" International Journal of Molecular Sciences 22, no. 1: 271. https://doi.org/10.3390/ijms22010271

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