Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway

Kidney Int. 2017 Mar;91(3):642-657. doi: 10.1016/j.kint.2016.09.036. Epub 2016 Dec 1.


Pigment epithelium-derived factor (PEDF) expression is downregulated in the kidneys of diabetic rats, and delivery of PEDF suppressed renal fibrotic factors in these animals. PEDF has multiple functions including anti-angiogenic, anti-inflammatory and antifibrotic activities. Since the mechanism underlying its antifibrotic effect remains unclear, we studied this in several murine models of renal disease. Renal PEDF levels were significantly reduced in genetic models of type 1 and type 2 diabetes (Akita and db/db, respectively), negatively correlating with Wnt signaling activity in the kidneys. In unilateral ureteral obstruction, an acute renal injury model, there were significant decreases of renal PEDF levels. The kidneys of PEDF knockout mice with ureteral obstruction displayed exacerbated expression of fibrotic and inflammatory factors, oxidative stress, tubulointerstitial fibrosis, and tubule epithelial cell apoptosis, compared to the kidneys of wild-type mice with obstruction. PEDF knockout enhanced Wnt signaling activation induced by obstruction, while PEDF inhibited the Wnt pathway-mediated fibrosis in primary renal proximal tubule epithelial cells. Additionally, oxidative stress was aggravated in renal proximal tubule epithelial cells isolated from knockout mice and suppressed by PEDF treatment of renal proximal tubule epithelial cells. PEDF also reduced oxidation-induced apoptosis in renal proximal tubule epithelial cells. Thus, the renoprotective effects of PEDF are mediated, at least partially, by inhibition of the Wnt pathway. Hence, restoration of renal PEDF levels may have therapeutic potential for renal fibrosis.

Keywords: PEDF; Wnt pathway; fibrosis; inflammation; kidney; oxidative stress; renal tubule epithelial cells; renoprotective; β-catenin.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Axin Protein / genetics
  • Axin Protein / metabolism
  • Cell Line
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control
  • Disease Models, Animal
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Fibrosis
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Humans
  • Inflammation Mediators / metabolism
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Diseases / prevention & control*
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Growth Factors / deficiency
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Oxidative Stress
  • Phenotype
  • Serpins / deficiency
  • Serpins / genetics
  • Serpins / metabolism*
  • Time Factors
  • Transfection
  • Ureteral Obstruction / complications
  • Ureteral Obstruction / genetics
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology
  • Wnt Signaling Pathway*


  • Axin Protein
  • Axin2 protein, mouse
  • Eye Proteins
  • Inflammation Mediators
  • Nerve Growth Factors
  • Serpins
  • pigment epithelium-derived factor