Integrin linked kinase regulates the transcription of AQP2 by NFATC3

Biochim Biophys Acta Gene Regul Mech. 2017 Sep;1860(9):922-935. doi: 10.1016/j.bbagrm.2017.07.006. Epub 2017 Jul 20.

Abstract

Two processes are associated with progressive loss of renal function: 1) decreased aquaporin-2 (AQP2) expression and urinary concentrating capacity (Nephrogenic Diabetes Insipidus, NDI); and 2) changes in extracellular matrix (ECM) composition, e.g. increased collagen I (Col I) deposition, characteristic of tubule-interstitial fibrosis. AQP2 expression is regulated by both the ECM-to-intracellular scaffold protein integrin-linked kinase (ILK) by NFATc/AP1 and other transcription factors. In the present work, we used in vivo and in vitro approaches to examine ILK participation in NFATc3/AP-1-mediated increases in AQP2 gene expression. Both NFATc3 knock-out mice and ILK conditional-knockdown mice (cKD-ILK) display symptoms of NDI (polyuria and reduced AQP2 expression). NFATc3 is upregulated in the renal medulla tubular cells of cKD-ILK mice but with reduced nuclear localization. Inner medullary collecting duct mIMCD3 cells were subjected to ILK depletion and transfected with reporter plasmids. Pharmacological activators or inhibitors determined the effect of ILK activity on NFATc/AP-1-dependent increases in transcription of AQP2. Finally, mIMCD3 cultured on Col I showed reduced activity of the ILK/GSK3β/NFATc/AQP2 axis, suggesting this pathway is a potential target for therapeutic treatment of NDI.

Keywords: Aquaporin 2; Extracellular matrix; GSK3β; Integrin linked kinase; NFATc3; Nephrogenic Diabetes Insipidus.

MeSH terms

  • Animals
  • Aquaporin 2 / genetics*
  • Cell Line
  • Diabetes Insipidus, Nephrogenic / genetics
  • Diabetes Insipidus, Nephrogenic / metabolism
  • Integrins / metabolism
  • Kidney Medulla / metabolism
  • Kidney Tubules, Collecting / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NFATC Transcription Factors / genetics*
  • Polyuria / genetics
  • Polyuria / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic / genetics*

Substances

  • Aqp2 protein, mouse
  • Aquaporin 2
  • Integrins
  • NFATC Transcription Factors
  • Nfatc3 protein, mouse
  • Transcription Factor AP-1
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases