title: Interaction between TGF-β and ACE2-Ang-(1-7)-Mas pathway in high glucose-cultured NRK-52E cells.
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.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan, ROC.
authors.forename: Chi-Hsien
authors.initials: CH
authors.lastname: Chou
authors.forename: Lea-Yea
authors.initials: LY
authors.lastname: Chuang
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Lu
authors.forename: Jinn-Yuh
authors.initials: JY
authors.lastname: Guh
mesh_terms: D000595:Amino Acid Sequence; D000803:Angiotensin I / Q000737:chemistry / Q000378:metabolism*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism; D018374:LLC-PK1 Cells; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000803:Angiotensin I; D000804:Angiotensin II; D000085962:Angiotensin-Converting Enzyme 2; D001549:Benzamides; D002867:Chromones; D004149:Dioxoles; D005353:Fibronectins; D005947:Glucose; D053614:Janus Kinase 2; D009025:Morpholines; D010446:Peptide Fragments; D007703:Peptidyl-Dipeptidase A; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000077293:Receptor, Transforming Growth Factor-beta Type I; D043562:Receptors, G-Protein-Coupled; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D020032:Tyrphostins; C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C092006:7-Ala-angiotensin (1-7); C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000625843:Tgfbr1 protein, rat; C000705329:Ace2 protein, rat; C118790:angiotensin I (1-7)