Interaction between TGF-β and ACE2-Ang-(1-7)-Mas pathway in high glucose-cultured NRK-52E cells

Mol Cell Endocrinol. 2013 Feb 5;366(1):21-30. doi: 10.1016/j.mce.2012.11.004. Epub 2012 Nov 19.

Abstract

Transforming growth factor-β (TGF-β) is pivotal in diabetic nephropathy (DN). Angiotensin converting enzyme-2 (ACE2) converts angiotensin II (Ang II) to angiotensin 1-7 (Ang-(1-7)), which binds to Mas. Proximal tubular ACE2 is decreased in DN. ACE2 deficiency exacerbates whereas ACE2 overexpression attenuates DN. Thus, we investigated the mechanism of high glucose-decreased ACE2 in terms of the interaction between TGF-β and ACE2-Ang-(1-7)-Mas in NRK-52E cells. We found that high glucose increased TGF-β1. SB431542 attenuated high glucose-inhibited ACE2 and Mas and Ang-(1-7) conversion from Ang II while attenuating high glucose-induced fibronectin. TGF-β1 also decreased ACE2 and Mas and Ang-(1-7) conversion from Ang II. A779 attenuated Ang-(1-7)-decreased TGF-β1 and Ang-(1-7)-activated JAK2-STAT3. Moreover, A779, LY294002 and AG490 attenuated Ang-(1-7)-inhibited TGF-β1. The combination of Ang-(1-7) and Mas attenuated TGF-β1 (but not high glucose)-induced fibronectin. Thus, high glucose decreases ACE2 via TGF-βR in NRK-52E cells. Additionally, there is a negative feedback function between TGF-β and ACE2, and the combined inhibition of TGF-β and activation of the ACE2-Ang-(1-7)-Mas may be useful for treating diabetic renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Angiotensin I / chemistry
  • Angiotensin I / metabolism*
  • Angiotensin II / analogs & derivatives
  • Angiotensin II / pharmacology
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Benzamides / pharmacology
  • Cells, Cultured
  • Chromones / pharmacology
  • Dioxoles / pharmacology
  • Fibronectins / metabolism
  • Gene Expression Regulation / drug effects
  • Glucose / pharmacology*
  • Janus Kinase 2 / metabolism
  • LLC-PK1 Cells
  • Molecular Sequence Data
  • Morpholines / pharmacology
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Peptidyl-Dipeptidase A / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects*
  • Swine
  • Transcription, Genetic / drug effects
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tyrphostins / pharmacology

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • 7-Ala-angiotensin (1-7)
  • Benzamides
  • Chromones
  • Dioxoles
  • Fibronectins
  • Morpholines
  • Peptide Fragments
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Angiotensin II
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Angiotensin I
  • Janus Kinase 2
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Tgfbr1 protein, rat
  • Peptidyl-Dipeptidase A
  • Ace2 protein, rat
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)
  • Glucose