Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

Autophagy. 2016 Jun 2;12(6):976-98. doi: 10.1080/15548627.2016.1166317. Epub 2016 Apr 28.

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.

Keywords: Autophagy; kidney injury; proximal tubule; renal fibrosis; unilateral ureteral obstruction.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • Autophagy* / drug effects
  • Autophagy-Related Protein 7 / metabolism
  • Beclin-1 / chemistry
  • Beclin-1 / pharmacology
  • Cell Line
  • Fibronectins / metabolism
  • Fibrosis
  • Inflammation / complications
  • Inflammation / pathology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / pathology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Oligopeptides / pharmacology
  • Phenotype
  • TOR Serine-Threonine Kinases / metabolism
  • Transforming Growth Factor beta1 / pharmacology
  • Ureteral Obstruction / complications
  • Ureteral Obstruction / pathology*

Substances

  • Beclin-1
  • Fibronectins
  • Multiprotein Complexes
  • Oligopeptides
  • Transforming Growth Factor beta1
  • benzyloxycarbonyl-valyl-alanyl-aspartic acid
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Autophagy-Related Protein 7