title: AT2R agonist, compound 21, is reno-protective against type 1 diabetic nephropathy.
abstract: The hemodynamic and nonhemodynamic effects of angiotensin II on diabetic complications are considered to be primarily mediated by the angiotensin II type 1 receptor subtype. However, its biological and functional effect mediated through the angiotensin II type 2 receptor subtype is still unclear. Activation of the angiotensin II type 2 receptors has been postulated to oppose angiotensin II type 1 receptor-mediated actions and thus attenuate fibrosis. This study aimed to elucidate the reno-protective role of the novel selective angiotensin II type 2 receptor agonist, Compound 21, in an experimental model of type 1 diabetic nephropathy. Compound 21 treatment significantly attenuated diabetes mellitus-induced elevated levels of cystatin C, albuminuria, mesangial expansion, and glomerulosclerosis in diabetic mice. Moreover, Compound 21 markedly inhibited the expression of various proteins implicated in oxidative stress, inflammation, and fibrosis, in association with decreased extracellular matrix production. These findings demonstrate that monotherapy of Compound 21 is protective against the progression of experimental diabetic nephropathy by inhibiting renal oxidative stress, inflammation, and fibrosis.
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Christine
authors.initials: C
authors.lastname: Koulis
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Bryna S M
authors.initials: BS
authors.lastname: Chow
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Maria
authors.initials: M
authors.lastname: McKelvey
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Steckelings
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.).
authors.forename: Karin A
authors.initials: KA
authors.lastname: Jandeleit-Dahm
authors.affiliation: From the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.K., B.S.M.C., M.M., V.T.-B., M.C.T., M.E.C., K.A.J.-D., T.J.A.); the Department of Medicine, Monash University, Monash, Australia (M.C.T., M.E.C., K.A.J.-D., T.J.A.); IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Denmark (U.M.S.); and CARIM-School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands (T.U.). terri.allen@bakeridi.edu.au.
authors.forename: Terri J
authors.initials: TJ
authors.lastname: Allen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007150:Immunohistochemistry; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes
keywords: AT2 receptor; angiotensin II; compound 21; diabetic nephropathy; kidney