SREBP inhibition ameliorates renal injury after unilateral ureteral obstruction

Am J Physiol Renal Physiol. 2016 Sep 1;311(3):F614-25. doi: 10.1152/ajprenal.00140.2016. Epub 2016 Jul 6.

Abstract

Tubulointerstitial fibrosis is a major feature associated with declining kidney function in chronic kidney disease of diverse etiology. No effective means as yet exists to prevent the progression of fibrosis. We have shown that the transcription factor sterol-regulatory element-binding protein 1 (SREBP-1) is an important mediator of the profibrotic response to transforming growth factor-β (TGF-β) and angiotensin II, both key cytokines in the fibrotic process. Here, we examined the role of SREBP in renal interstitial fibrosis in the unilateral ureteral obstruction (UUO) model. The two isoforms of SREBP (-1 and -2) were activated by 3 days after UUO, with SREBP-1 showing a more sustained activation to 21 days. We then examined whether SREBP1/2 inhibition with the small-molecule inhibitor fatostatin could attenuate fibrosis after 14 days of UUO. SREBP activation was confirmed to be inhibited by fatostatin. Treatment decreased interstitial fibrosis, TGF-β signaling, and upregulation of α-smooth muscle actin (SMA), a marker of fibroblast activation. Fatostatin also attenuated inflammatory cell infiltrate and apoptosis. Associated with this, fatostatin preserved proximal tubular mass. The significant increase in atubular glomeruli observed after UUO, known to correlate with irreversible renal functional decline, was also decreased by treatment. In cultured primary fibroblasts, TGF-β1 induced the activation of SREBP-1 and -2. Fatostatin blocked TGF-β1-induced α-SMA and matrix protein upregulation. The inhibition of SREBP is thus a potential novel therapeutic target in the treatment of fibrosis in chronic kidney disease.

Keywords: inflammation; interstitial fibrosis; sterol regulatory element-binding protein (SREBP); transforming growth factor-β (TGF-β); unilateral ureteral obstruction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Signal Transduction / drug effects
  • Sterol Regulatory Element Binding Proteins / antagonists & inhibitors*
  • Sterol Regulatory Element Binding Proteins / metabolism
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use*
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation / drug effects
  • Ureteral Obstruction / drug therapy*
  • Ureteral Obstruction / metabolism
  • Ureteral Obstruction / pathology

Substances

  • Pyridines
  • Sterol Regulatory Element Binding Proteins
  • Thiazoles
  • Transforming Growth Factor beta
  • fatostatin