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Title: | Cyclophilin D promotes tubular cell damage and the development of interstitial fibrosis in the obstructed kidney. | Authors: | Nikolic-Paterson D.J. ;Hou W.;Leong K.G.;Ozols E.;Tesch G.H.;Ma F.Y. | Institution: | (Hou) Department of Nephrology, Xinqiao Hospital, Chongqing, China (Leong, Ozols, Tesch, Nikolic-Paterson, Ma) Department of Nephrology, Monash Health, Monash Medical Centre, Clayton, VIC, Australia (Leong, Ozols, Tesch, Nikolic-Paterson, Ma) Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, Australia | Issue Date: | 20-Feb-2018 | Copyright year: | 2018 | Publisher: | Blackwell Publishing | Place of publication: | Australia | Publication information: | Clinical and Experimental Pharmacology and Physiology. 45 (3) (pp 250-260), 2018. Date of Publication: March 2018. | Journal: | Clinical and Experimental Pharmacology and Physiology | Abstract: | Cyclophilin D (CypD) is an important component in mitochondrial-dependent tubular cell death in acute kidney injury. However, it is not known whether CypD contributes to tubular cell damage in chronic interstitial fibrosis. We investigated this question in the unilateral ureter obstruction (UUO) model of renal interstitial fibrosis. Groups of CypD-/- and wild type (WT) mice were killed 7 or 12 days after UUO surgery. The significant tubular cell apoptosis seen in WT UUO was significantly reduced in CypD-/- UUO based on TUNEL and cleaved caspase 3 staining. Other markers of tubular cell damage; loss of E-cadherin and AQP1 expression, were also reduced in the CypD-/- UUO kidney. This reduced tubular damage was associated with less inflammation and a partial protection against loss of peritubular capillaries. The prominent accumulation of alpha-SMA+ myofibroblasts and interstitial collagen deposition seen in WT UUO was significantly reduced in CypD-/- UUO on day 12, but not day 7. Activation of several pro-fibrotic signalling pathways (p38 MAPK, JNK and Smad3) was unaltered in CypD-/- UUO, arguing that CypD acts independently to promote renal fibrosis. CypD deletion in cultured tubular cells attenuated oxidative stress-induced pro-inflammatory, pro-fibrotic and apoptotic responses; however, responses to angiotensin II and LPS were unaffected. In contrast, CypD deletion in cultured renal fibroblasts did not affect PDGF-induced proliferation or TGF-beta1-induced collagen I expression, suggesting no direct role of CypD in the fibroblast response. In conclusion, we have identified a role for CypD in chronic tubular cell damage and in the development of renal interstitial fibrosis.Copyright © 2017 John Wiley & Sons Australia, Ltd | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1111/1440-1681.12881 | ORCID: | Nikolic-Paterson, David J; ORCID: http://orcid.org/0000-0001-5734-2931 | Link to associated publication: | Click here for full text options | PubMed URL: | 29230844 [http://www.ncbi.nlm.nih.gov/pubmed/?term=29230844] | ISSN: | 0305-1870 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/37125 | Type: | Article | Subjects: | mouse myofibroblast nonhuman obstruction-induced renal fibrosis oxidative stress protein cleavage protein expression TUNEL assay *ureter obstruction alpha smooth muscle actin/ec [Endogenous Compound] angiotensin II/ec [Endogenous Compound] aquaporin 1/ec [Endogenous Compound] caspase 3/ec [Endogenous Compound] CD68 antigen/ec [Endogenous Compound] collagen type 1/ec [Endogenous Compound] collagen type 4/ec [Endogenous Compound] *cyclophilin D/ec [Endogenous Compound] Janus kinase/ec [Endogenous Compound] kidney injury molecule 1/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] Smad3 protein/ec [Endogenous Compound] survivin/ec [Endogenous Compound] transforming growth factor beta1 tubulin/ec [Endogenous Compound] uvomorulin/ec [Endogenous Compound] vasculotropin A/ec [Endogenous Compound] signal transduction mitogen activated protein kinase p38/ec [Endogenous Compound] monocyte chemotactic protein 1/ec [Endogenous Compound] platelet derived growth factor platelet derived growth factor B/ec [Endogenous Compound] protein kinase B/ec [Endogenous Compound] reduced nicotinamide adenine dinucleotide phosphate oxidase 4/ec [Endogenous Compound] animal experiment animal model animal tissue apoptosis article cell proliferation controlled study fibroblast *fibrosing alveolitis kidney function *kidney tubule cell male obstruction-induced renal fibrosis oxidative stress protein cleavage protein expression signal transduction TUNEL assay *ureter obstruction Article apoptosis mouse animal tissue male animal model animal experiment *kidney tubule cell cell proliferation nonhuman kidney function *fibrosing alveolitis fibroblast controlled study myofibroblast |
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