title: Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy.
abstract: Enhanced renal expression for the renin-angiotensin system (RAS) is detected in IgA nephropathy (IgAN). Previous data showed an altered glomerular expression of angiotensin II type 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN. In this study, the expression and regulation of Ang II receptors were examined in human proximal tubular epithelial cells (PTEC) in IgAN. Tubular expression of AT1R and Ang II type 2 receptor (AT2R) was increased in IgAN. In vitro culture experiment showed that the upregulation of Ang II receptors was not due to the direct effect of IgA but the indirect effect after IgA deposition on human mesangial cell. When PTEC were cultured with conditioned culture medium from human mesangial cells activated with IgA, Ang II production was upregulated, leading to inflammation and apoptosis via the AT1R and AT2R, respectively. Sequential expression of Ang II receptors determined the injury of PTEC induced by mediators in the conditioned medium. The initial interaction between Ang II and AT1R activated both protein kinase C and mitogen-activated protein kinase pathways, leading to inflammatory responses. This early AT1R-dependent event was followed by upregulation of AT2R expression and continued Ang II release. The interaction between Ang II and AT2R subsequently led to expression of cleaved poly[ADP-ribose] polymerase through downregulation of the mitogen-activated protein kinase pathway. The data suggest that appropriate control of Ang II receptor activities in PTEC may ameliorate tubulointerstitial injury in IgAN.
authors.affiliation: Department of Medicine, Room 411, Professorial Block, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
authors.forename: Cindy B Y
authors.initials: CB
authors.lastname: Choy
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
mesh_terms: D000804:Angiotensin II; D017209:Apoptosis; D002478:Cells, Cultured / Q000166:cytology; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D005922:Glomerulonephritis, IGA / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007070:Immunoglobulin A / Q000737:chemistry / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis; D007674:Kidney Diseases / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007700:Kinetics; D019808:Losartan / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D050527:Mesangial Cells / Q000166:cytology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D011493:Protein Kinase C / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; D007093:Imidazoles; D007070:Immunoglobulin A; D015850:Interleukin-6; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C073402:PD 123319; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019808:Losartan