title: Phosphate-Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1.
abstract: Tubulo-interstitial fibrosis is a common, destructive endpoint for a variety of kidney diseases. Fibrosis is well correlated with the loss of kidney function in both humans and rodents. The identification of modulators of fibrosis could provide novel therapeutic approaches to reducing disease progression or severity. Here, we show that the peptidyl-prolyl isomerase Pin1 is an important molecular contributor that facilitates renal fibrosis in a well-characterized animal model. While wild-type mice fed a high phosphate diet (HPD) for 8-12 weeks developed calcium deposition, macrophage infiltration and extracellular matrix (ECM) accumulation in the kidney interstitium, Pin1 null mice showed significantly less pathology. The serum Pi in both WT and KO mice were significantly increased by the HPD, but the serum Ca was slightly decreased in KO compared to WT. In addition, both WT and KO HPD mice had less weight gain but exhibited normal organ mass (kidney, lung, spleen, liver and heart). Unexpectedly, renal function was not initially impaired in either genotype irrespective of the HPD. Our results suggest that diet containing high Pi induces rapid renal fibrosis before a significant impact on renal function and that Pin1 plays an important role in the fibrotic process.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Zhong-Jian
authors.initials: ZJ
authors.lastname: Shen
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiizaki
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
mesh_terms: D000818:Animals; D002118:Calcium / Q000097:blood; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000473:pathology; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics*; D010710:Phosphates / Q000008:administration & dosage / Q000097:blood; D015430:Weight Gain / Q000235:genetics
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010710:Phosphates; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D002118:Calcium