Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney

Am J Physiol Renal Physiol. 2018 May 1;314(5):F753-F762. doi: 10.1152/ajprenal.00528.2017. Epub 2017 Nov 29.

Abstract

In a new paradigm of etiology related to chronic kidney disease-mineral and bone disorder (CKD-MBD), kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while activin A might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in the obstructed kidney, untouched contralateral kidney, and vasculature which might be affected by secreted factors from the obstructed kidney, and comparing with unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene and protein depletion, whereas plasma Klotho increased in both UUO and UNX rats, indicating an altered metabolism of Klotho. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of the examined fibrosis-related genes, as did remnant UNX kidneys. UUO caused upregulation of transforming growth factor-β and induction of periostin and activin A in obstructed kidneys without changes in the contralateral kidneys. Plasma activin A doubled in UUO rats after 10 days while no changes were seen in UNX rats, suggesting secretion of activin A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats compared with UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis, supporting the existence of a new kidney-vasculature axis.

Keywords: Klotho; Wnt; activin A; renal fibrosis; unilateral ureter obstruction.

Publication types

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

MeSH terms

  • Acute Kidney Injury / blood*
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / physiopathology
  • Animals
  • Aorta / metabolism
  • Biomarkers / blood
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Chronic Kidney Disease-Mineral and Bone Disorder / blood*
  • Chronic Kidney Disease-Mineral and Bone Disorder / pathology
  • Chronic Kidney Disease-Mineral and Bone Disorder / physiopathology
  • Disease Models, Animal
  • Fibrosis
  • Gene Expression Regulation
  • Genetic Markers / genetics
  • Glucuronidase / blood*
  • Glucuronidase / genetics
  • Inhibin-beta Subunits / blood*
  • Inhibin-beta Subunits / genetics
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney / physiopathology
  • Klotho Proteins
  • Male
  • Rats, Wistar
  • Signal Transduction
  • Time Factors
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Ureteral Obstruction / blood*
  • Ureteral Obstruction / pathology
  • Ureteral Obstruction / physiopathology

Substances

  • Biomarkers
  • Bone Morphogenetic Proteins
  • Cell Adhesion Molecules
  • Genetic Markers
  • Postn protein, rat
  • Sost protein, rat
  • Transforming Growth Factor beta
  • inhibin beta A subunit
  • Inhibin-beta Subunits
  • Glucuronidase
  • Klotho Proteins