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Title: | Cyclophilin inhibition protects against experimental acute kidney injury and renal interstitial fibrosis. | Authors: | Ozols E.;Nikolic-Paterson D.J. ;Ma F.Y.;Liles J.T.;Badal S.S.;Kanellis J.;Leong K.G. | Monash Health Department(s): | Nephrology | Institution: | (Leong, Ozols, Kanellis, Nikolic-Paterson, Ma) Monash Medical Centre, Department of Nephrology, Clayton, VIC 3168, Australia (Leong, Ozols, Kanellis, Nikolic-Paterson, Ma) Centre for Inflammatory Diseases, Monash University, Clayton, VIC 3168, Australia (Badal, Liles) Gilead Sciences, Foster City, CA 94404, United States | Issue Date: | 26-Jan-2021 | Copyright year: | 2021 | Publisher: | MDPI AG | Place of publication: | Switzerland | Publication information: | International Journal of Molecular Sciences. 22 (1) (pp 1-19), 2021. Article Number: 271. Date of Publication: 01 Jan 2021. | Journal: | International Journal of Molecular Sciences | Abstract: | Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochon-drial-dependent cell death. This study investigated the therapeutic potential of a selective cyclo-philin 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 signifi-cantly 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.Copyright © 2020 by the authors. | DOI: | http://monash.idm.oclc.org/login?url= http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.3390/ijms22010271 |
PubMed URL: | 33383945 [http://www.ncbi.nlm.nih.gov/pubmed/?term=33383945] | ISSN: | 1661-6596 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/28557 | Type: | Article | Subjects: | kidney function kidney tubule cell kidney tubule necrosis macrophage migration male mouse mRNA expression level myofibroblast neutrophil chemotaxis nonhuman primary culture renal ischemia reperfusion injury *renal protection alpha smooth muscle actin/ec [Endogenous Compound] buprenorphine/sc [Subcutaneous Drug Administration] carprofen/sc [Subcutaneous Drug Administration] CD68 antigen/ec [Endogenous Compound] collagen type 4/ec [Endogenous Compound] *cyclophilin/ec [Endogenous Compound] cyclophilin A/ec [Endogenous Compound] cyclophilin D/ec [Endogenous Compound] *cyclophilin inhibitor/cr [Drug Concentration] *cyclophilin inhibitor/do [Drug Dose] *cyclophilin inhibitor/dt [Drug Therapy] *cyclophilin inhibitor/po [Oral Drug Administration] *cyclophilin inhibitor/pd [Pharmacology] interleukin 2/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] mitogen activated protein kinase p38/ec [Endogenous Compound] monocyte chemotactic protein 1/ec [Endogenous Compound] neutrophil gelatinase associated lipocalin/ec [Endogenous Compound] oxygen radical platelet derived growth factor B/ec [Endogenous Compound] stress activated protein kinase/ec [Endogenous Compound] transforming growth factor beta1/ec [Endogenous Compound] tubulin tumor necrosis factor/ec [Endogenous Compound] unclassified drug *gs 642362/cr [Drug Concentration] *gs 642362/do [Drug Dose] *gs 642362/dt [Drug Therapy] *gs 642362/po [Oral Drug Administration] *gs 642362/pd [Pharmacology] ureter obstruction *acute kidney failure/dt [Drug Therapy] animal cell animal experiment animal model animal tissue article cell death controlled study dose response drug blood level drug dose comparison drug efficacy EC90 *enzyme inhibition experimental renal failure glomerulus capillary immunohistochemistry in vivo study *kidney fibrosis/dt [Drug Therapy] drug efficacy EC90 *enzyme inhibition experimental renal failure glomerulus capillary immunohistochemistry in vivo study *kidney fibrosis / *drug therapy kidney function kidney tubule cell kidney tubule necrosis macrophage migration male mouse mRNA expression level myofibroblast neutrophil chemotaxis nonhuman primary culture renal ischemia reperfusion injury *renal protection animal experiment animal cell *acute kidney failure / *drug therapy ureter obstruction animal model animal tissue Article cell death controlled study dose response drug blood level drug dose comparison |
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