title: Surfactant protein A deficiency exacerbates renal interstitial fibrosis following obstructive injury in mice.
abstract: Renal interstitial fibrosis is an inevitable consequence of virtually every type of chronic kidney disease. The underlying mechanisms, however, are not completely understood. In the present study, we identified surfactant protein A (SP-A) as a novel protein factor involved in the renal fibrosis induced by unilateral ureter obstruction (UUO). UUO induced SP-A expression in mouse kidney epithelium, likely due to the increased acidic stress and inflammation. Interestingly, SP-A deficiency aggravated UUO-prompted kidney structural damage, macrophage accumulation, and tubulointerstitial fibrosis. SP-A deficiency appeared to worsen the fibrosis by enhancing interstitial myofibroblast accumulation. Moreover, SP-A deficiency increased the expression of TGF-β1, the major regulator of kidney fibrosis, particularly in the interstitial cells. Mechanistically, SP-A deficiency increased the expression and release of high mobility group box 1 (HMGB1), a factor regulating TGF-β expression/signaling and implicated in renal fibrosis. SP-A also blocked HMGB1 activities in inducing TGF-β1 expression and myofibroblast transdifferentiation from kidney fibroblasts, demonstrating that SP-A protected kidney by impeding both the expression and fibrogenic function of HMGB1. Since SP-A physically interacted with HMGB1 both in vitro and in kidney tissue in vivo, SP-A may exert its protective role by binding to HMGB1 and thus titrating its activity during UUO-induced renal fibrosis.
authors.affiliation: Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA; Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China. Electronic address: sc229@uga.edu.
authors.forename: Shaojiang
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA.
authors.forename: Chenxiao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA; Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Ran
authors.affiliation: Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA; Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D024243:HMGB1 Protein; D037662:Pulmonary Surfactant-Associated Protein A
keywords: High mobility group box 1; Kidney fibrosis; Myofibroblast activation; Surfactant protein A; TGF-β; Unilateral ureter obstruction