title: Enhanced angiotensin-converting enzyme 2 attenuates angiotensin II-induced collagen production via AT1 receptor-phosphoinositide 3-kinase-Akt pathway.
abstract: Recent reports support a protective role for angiotensin-converting enzyme 2 (ACE2) against glomerular diseases, especially by decreasing of extracellular matrix (ECM) proteins. However, the mechanism regulating this effect appears to be complex and poorly understood. Our aim was to investigate whether or not ACE2 ameliorates the profibrotic effects of Ang II-mediated, Akt-dependent pathways in the mouse mesangial cell line, MES-13.Gene transfer of ACE2 suppressed Ang II-activated Akt-phosphorylation, accompanied by a decreased level of collagen type I in cells. In addition, Ang II-induced collagen type I synthesis in MES-13s by activating the Ang II/AT-1R-PI3K pathway. This transactivation was dependent on cAMP/Epac but not on PKA. TGF-βRI played a pivotal role in this signaling pathway inducing collagen deposition effects which could be reversed by ACE2 gene transfer in MES-13 cells. The results revealed that gene transfer of ACE2 regulated Ang II-mediated AT1R-TGFβRI-PI3K-Akt signaling and involved the synthesis of collagen. The beneficial effect of ACE2 overexpression appeared to result mainly from blocking phosphorylation of Akt in mesangial cells, suggesting that the ACE2 gene might be a novel therapeutic target for glomerular diseases.
authors.affiliation: Department of Endocrinology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, China. bule198311@hotmail.com
authors.forename: Le
authors.initials: L
authors.lastname: Bu
authors.forename: Shen
authors.initials: S
authors.lastname: Qu
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: J-J
authors.initials: JJ
authors.lastname: Zou
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: L-L
authors.initials: LL
authors.lastname: Sun
authors.forename: Z-M
authors.initials: ZM
authors.lastname: Liu
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000803:Angiotensin I; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D007676:Kidney Failure, Chronic / Q000517:prevention & control; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000803:Angiotensin I; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D000085962:Angiotensin-Converting Enzyme 2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010446:Peptide Fragments; D007703:Peptidyl-Dipeptidase A; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; C000705328:Ace2 protein, mouse; C118790:angiotensin I (1-7)