title: Angiotensin II Type 2 Receptor Decreases Transforming Growth Factor-β Type II Receptor Expression and Function in Human Renal Proximal Tubule Cells.
abstract: Transforming growth factor-β (TGF-β), via its receptors, induces epithelial-mesenchymal transition (EMT) and plays an important role in the development of renal tubulointersitial fibrosis. Angiotensin II type 2 receptor (AT2R), which mediates beneficial renal physiological functions, has received attention as a prospective therapeutic target for renoprotection. In this study, we investigated the effect and underlying mechanism of AT2R on the TGF-β receptor II (TGF-βRII) expression and function in human proximal tubular cells (HK-2). Here, we show that the AT2R agonist CGP42112A decreased TGF-βRII protein expression in a concentration- and time-dependent manner in HK-2 cells. The inhibitory effect of the AT2R on TGF-βRII expression was blocked by the AT2R antagonists PD123319 or PD123177. Stimulation with TGF-β1 enhanced EMT in HK-2 cells, which was prevented by pre-treatment with CGP42112A. One of mechanisms in this regulation is associated with the increased TGF-βRII degradation after activation of AT2R. Furthermore, laser confocal immunofluorescence microscopy showed that AT2R and TGF-βRII colocalized in HK-2 cells. AT2R and TGF-βRII coimmunoprecipitated and this interaction was increased after AT2R agonist stimulation for 30 min. The inhibitory effect of the AT2R on TGF-βRII expression was also blocked by the nitric oxide synthase inhibitor L-NAME, indicating that nitric oxide is involved in the signaling pathway. Taken together, our study indicates that the renal AT2R regulates TGF-βRII expression and function via the nitric oxide pathway, which may be important in the control of renal tubulointerstitial fibrosis.
authors: Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
authors: Hui-Lin
authors: HL
authors: Guo
authors: Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
authors: Xiao-Hui
authors: XH
authors: Liao
authors: Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
authors: Qi
authors: Q
authors: Liu
authors: Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
authors: Ling
authors: L
authors: Zhang
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007668:Kidney / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000473:pathology*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009569:Nitric Oxide / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism* / Q000502:physiology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D018125:Receptors, Transforming Growth Factor beta; C066253:PD 123177; C060894:CGP 42112A; C073402:PD 123319; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II