title: Blockade of cysteine-rich protein 61 attenuates renal inflammation and fibrosis after ischemic kidney injury.
abstract: Emerging data have suggested that acute kidney injury (AKI) is often incompletely repaired and can lead to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. However, the underlying mechanisms linking AKI to CKD remain obscure. The present study aimed to investigate the role of cysteine-rich protein 61 (Cyr61) after unilateral kidney ischemia-reperfusion injury (IRI) in mice. After IRI, increased expression of Cyr61 was detected, predominately in the proximal tubular epithelium. This was confirmed by in vitro experiments, which showed that hypoxia stimulated Cyr61 expression in cultured proximal tubular epithelial cells. The proinflammatory property of Cyr61 was indicated by its ability to upregulate monocyte chemoattractant protein-1 and IL-6. Additionally, we found elevated urinary Cyr61 excretion in patients with AKI. Notably, treatment of mice with an anti-Cyr61 antibody attenuated the upregulation of kidney monocyte chemoattractant protein-1, IL-6, IL-1β, and macrophage inflammatory protein-2 and reduced the infiltration of F4/80-positive macrophages on days 7 and 14 after IRI. In addition, blockade of Cyr61 reduced the mRNA expression of collagen, transforming growth factor-β, and plasminogen activator inhibitor-I as well as the degree of collagen fibril accumulation, as evaluated by picrosirius red staining, and levels of α-smooth muscle actin proteins by day 14. Concurrently, in the treated group, peritubular microvascular density was more preserved on day 14. We conclude that Cyr61 blockade inhibits the triad of inflammation, interstitial fibrosis, and capillary rarefaction after severe ischemic AKI. The results of this study expand the knowledge of the mechanisms underlying the AKI-to-CKD transition and suggest that Cyr61 is a potential therapeutic target.
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan;
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Lai
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan;
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan;
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Chiang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou City, Taiwan;
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan;
authors.forename: Vin-Cent
authors.initials: VC
authors.lastname: Wu
authors.affiliation: Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and.
authors.forename: Guang-Huar
authors.initials: GH
authors.lastname: Young
authors.affiliation: Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and.
authors.forename: Wen-Jo
authors.initials: WJ
authors.lastname: Ko
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University College of Life Science, Taipei, Taiwan.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; tjtsai@ntuh.gov.tw.
authors.forename: Tun-Jun
authors.initials: TJ
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan;
authors.forename: Kwan-Dun
authors.initials: KD
authors.lastname: Wu
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D000860:Hypoxia / Q000378:metabolism; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009393:Nephritis / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D058258:Serpin E2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; C491850:CCN1 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D055515:Cysteine-Rich Protein 61; D015850:Interleukin-6; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D016212:Transforming Growth Factor beta
keywords: acute kidney injury; cysteine-rich protein 61; fibrosis; inflammation; macrophages