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Relaxin-2 does not Ameliorate Nephropathy in an experimental model of Type-1 Diabetes

  • Background/Aims: In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide - is a candidate drug for both. Methods: Low-dose (32 mu g/kg/day) and high-dose (320 mu g/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Results: Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-beta pathway in thisBackground/Aims: In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide - is a candidate drug for both. Methods: Low-dose (32 mu g/kg/day) and high-dose (320 mu g/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Results: Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-beta pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. Conclusions: We investigated a model showing early DN without overt tubulo-interstitial fibrosis and activation of the TGF-beta-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes.show moreshow less

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Metadaten
Author:Thomas Bernd Dschietzig, Katharina Krause-Relle, Maud Hennequin, Karoline von Websky, Jan Rahnenfuhrer, Jana Ruppert, Hans Juergen Groena, Franz Paul Armbruster, Ross A. D. Bathgate, Joerg R. Aschenbach, Wolf-Georg Forssmann, Berthold HocherGND
DOI:https://doi.org/10.1159/000368484
ISSN:1420-4096 (print)
ISSN:1423-0143 (online)
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25791819
Parent Title (English):Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie
Publisher:Karger
Place of publication:Basel
Document Type:Article
Language:English
Year of first Publication:2015
Year of Completion:2015
Release Date:2017/03/27
Tag:Diabetic cardiomyopathy; Diabetic nephropathy; Fibrosis; Inflammation; Relaxin
Volume:40
Issue:1
Pagenumber:12
First Page:77
Last Page:88
Funder:German Ministry for Education and Research [AiF KF2181502FR9]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
Peer Review:Referiert
Publication Way:Open Access