title: Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction.
abstract: Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/α-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor β 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors.
authors.affiliation: a Department of Cellular Biology and Anatomy , Medical College of Georgia and Charlie Norwood VA Medical Center , Augusta , GA , USA.
authors.forename: Man J
authors.initials: MJ
authors.lastname: Livingston
authors.affiliation: b Cancer Center, Medical College of Georgia and Charlie Norwood VA Medical Center , Augusta , GA , USA.
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
authors.affiliation: c Department of Anatomy and Cell Biology , University of Florida College of Medicine , Gainesville , FL USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: d Division of Cardiology, Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: e Department of Pathology and Laboratory Medicine , Indiana University School of Medicine , Indianapolis , IN , USA.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
authors.affiliation: a Department of Cellular Biology and Anatomy , Medical College of Georgia and Charlie Norwood VA Medical Center , Augusta , GA , USA.|f Department of Nephrology , The Second Xiangya Hospital, Central South University , Changsha , China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism; D000071186:Beclin-1 / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010641:Phenotype; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000150:complications / Q000473:pathology*
chemical_list: D000071186:Beclin-1; D005353:Fibronectins; D046912:Multiprotein Complexes; D009842:Oligopeptides; D053773:Transforming Growth Factor beta1; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7
keywords: Autophagy; kidney injury; proximal tubule; renal fibrosis; unilateral ureteral obstruction