title: Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats.
abstract: The aim of this study was to evaluate the effect of compound 21 (C21), a selective AT2 receptor agonist, on diabetic nephropathy and the potential additive effect of C21, when associated with losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The experiments lasted 15 wk (from 5 to 20 wk of age) and were performed in 40 ZDF rats and 12 control lean rats. ZDF rats were divided into 4 groups: 1) 9 rats were treated with losartan; 2) 10 rats were treated with C21; 3) 9 rats were treated with losartan plus C21; and 4) 12 rats were maintained without any treatment. ZDF rats showed an increase in blood glucose level, albuminuria, renal fibrosis, macrophage infiltration, and TNF-α expression and a reduction of glomerular nephrin expression compared with control lean rats. C21 treatment reduced renal glomerular, tubulointerstitial, and perivascular fibrosis, and macrophage infiltration and TNF-α expression in ZDF rats. C21 treatment caused a decrease in albuminuria in ZDF rats up to 11 wk of age. Losartan decreased macrophage infiltration, TNF-α expression, and renal glomerular and perivascular fibrosis, restored glomerular nephrin expression, but did not affect tubulointerstitial fibrosis. Losartan treatment caused a decrease in albuminuria in ZDF rats up to 15 wk of age. At the end of the protocol, only the combination of C21 plus losartan significantly reduced albuminuria in ZDF rats. These data demonstrate that C21 has beneficial effects on diabetic nephropathy, suggesting the combination of C21 and losartan as a novel pharmacological tool to slow the progression of nephropathy in type II diabetes.
authors.affiliation: Clinica Nefrologica, Azienda Ospedaliera San Gerardo, Dipartimento di Scienze della Salute, Università degli Studi di Milano-Bicocca, Monza, Italy; giovanna.castoldi@unimib.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Castoldi
authors.affiliation: Istituto di Anatomia Patologica, Dipartimento di Scienze Radiologiche, Oncologiche e Anatomopatologiche, Sapienza Universita' di Roma, Rome, Italy;
authors.forename: Cira R T
authors.initials: CR
authors.lastname: di Gioia
authors.affiliation: Clinica Nefrologica, Azienda Ospedaliera San Gerardo, Dipartimento di Scienze della Salute, Università degli Studi di Milano-Bicocca, Monza, Italy;
authors.forename: Camila
authors.initials: C
authors.lastname: Bombardi
authors.affiliation: Unita' Complicanze del Diabete. Istituto Scientifico San Raffaele, Milan, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Maestroni
authors.affiliation: Istituto di Anatomia Patologica, Dipartimento di Scienze Radiologiche, Oncologiche e Anatomopatologiche, Sapienza Universita' di Roma, Rome, Italy;
authors.forename: Raffaella
authors.initials: R
authors.lastname: Carletti
authors.affiliation: IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark;
authors.forename: U Muscha
authors.initials: UM
authors.lastname: Steckelings
authors.affiliation: Department of Medicine, Sahlgrensha University Hospital/Ostra, Gothenburg. Sweden; and.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Dahlöf
authors.affiliation: CARIM, Maastricht University, Maastricht, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.affiliation: Unita' Complicanze del Diabete. Istituto Scientifico San Raffaele, Milan, Italy;
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Zerbini
authors.affiliation: Clinica Nefrologica, Azienda Ospedaliera San Gerardo, Dipartimento di Scienze della Salute, Università degli Studi di Milano-Bicocca, Monza, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Stella
mesh_terms: D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control* / Q000652:urine; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D016753:Interleukin-10 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D019808:Losartan; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D011924:Rats, Zucker; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; C113267:nephrin; D016753:Interleukin-10; D019808:Losartan
keywords: Zucker diabetic fatty rats; compound 21; diabetic nephropathy; experimental models; renal fibrosis; urinary albumin excretion