title: Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway.
abstract: 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.
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Xuemin
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Siribhinya
authors.initials: S
authors.lastname: Benyajati
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Moiseyev
authors.affiliation: Department of Cell Biology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Chengyi
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Cell Biology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Lorin E
authors.initials: LE
authors.lastname: Olson
authors.affiliation: Key Laboratory of Hormones and Development, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Section of Nephrology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Eby
authors.affiliation: Section of Nephrology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Lau
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. Electronic address: jian-xing-ma@ouhsc.edu.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D015843:Serpins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014517:Ureteral Obstruction / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D060466:Axin Protein; D005136:Eye Proteins; D018836:Inflammation Mediators; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C111729:Axin2 protein, mouse
keywords: PEDF; Wnt pathway; fibrosis; inflammation; kidney; oxidative stress; renal tubule epithelial cells; renoprotective; β-catenin