title: Oral Administration of N-Acetyl-seryl-aspartyl-lysyl-proline Ameliorates Kidney Disease in Both Type 1 and Type 2 Diabetic Mice via a Therapeutic Regimen.
abstract: Kidney fibrosis is the final common pathway of progressive kidney diseases including diabetic nephropathy. Here, we report that the endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), the substrate of angiotensin-converting enzyme (ACE), is an orally available peptide drug used to cure kidney fibrosis in diabetic mice. We utilized two mouse models of diabetic nephropathy, streptozotocin- (STZ-) induced type 1 diabetic CD-1 mice and type 2 diabetic nephropathy model db/db mice. Intervention with the ACE inhibitor imidapril, oral AcSDKP, or imidapril + oral AcSDKP combination therapy increased urine AcSDKP levels. AcSDKP levels were significantly higher in the combination group compared to those of the other groups. AcSDKP oral administration, either AcSDKP alone or in addition to imidapril, ameliorated glomerulosclerosis and tubulointerstitial fibrosis. Plasma cystatin C levels were higher in both models, at euthanasia, and were restored by all the treatment groups. The levels of antifibrotic miRs, such as miR-29 or let-7, were suppressed in the kidneys of both models; all treatments, especially the combination of imidapril + oral AcSDKP, restored the antifibrotic miR levels to a normal value or even higher. AcSDKP may be an oral antifibrotic peptide drug that would be relevant to combating fibroproliferative kidney diseases such as diabetic nephropathy.
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nitta
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Swayam Prakash
authors.initials: SP
authors.lastname: Srivastava
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa 078-8510, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D048289:Imidazolidines / Q000008:administration & dosage; D051379:Mice; D016688:Mice, Inbred NOD; D009842:Oligopeptides / Q000008:administration & dosage*; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism
chemical_list: D048289:Imidazolidines; D009842:Oligopeptides; C065166:imidapril; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; C058504:goralatide