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The Continuous Erythropoietin Receptor Activator Affects Different Pathways of Diabetic Renal Injury

Jan Menne^*, Joon-Keun Park^*, Nelli Shushakova^*, Michael Mengel, Matthias Meier^* and Danilo Fliser^*

^* Departments of Internal Medicine and Pathology, Hannover Medical School, Hannover, Germany

Correspondence: Dr. Danilo Fliser, Department of Internal Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Phone: +49-511-532-6319; Fax: +49-511-552366; E-mail: fliser.danilo{at}mh-hannover.de

Received for publication July 5, 2006. Accepted for publication April 18, 2007.

This study explored the tissue-protective properties of the continuous erythropoietin receptor activator (CERA) in an experimental model of (nonischemic) diabetic kidney injury (i.e., the db/db mouse). Mice were randomly treated with placebo (n = 25), low-dosage CERA (n = 25), and high-dosage CERA (n = 25). Also studied were 25 nondiabetic db/m mice. Hematocrit was comparable in placebo and low-dosage CERA–treated mice but increased significantly with high-dosage CERA (P < 0.01 versus both). Significantly reduced expression of TGF-, vascular endothelial growth factor, and collagen IV was found in glomeruli and the tubulointerstitial area with CERA treatment, and these beneficial molecular effects were clearly dosage dependent (both P < 0.05 versus placebo). Similarly, CERA treatment caused a dosage-dependent increase in p-Akt, nephrin, and perlecan tissue expression (all P < 0.05 versus placebo). However, the accelerated mesangial expansion that was observed in placebo-treated db/db mice (versus db/m controls) was significantly reduced only in low-dosage CERA–treated mice (P < 0.01). Moreover, albuminuria was significantly reduced in low- but not high-dosage CERA–treated mice compared with placebo treatment (P < 0.05). In an ancillary study, phlebotomy was performed in high-dosage CERA–treated db/db mice to keep hematocrit within normal (baseline) levels. This procedure resulted in significantly (P < 0.05) less albuminuria as compared with high-dosage CERA–treated mice without phlebotomy, thus preserving the tissue-protective potential of CERA. Long-term CERA treatment has beneficial dosage-dependent effects on molecular pathways of diabetic kidney damage. Low-dosage CERA does not affect hematocrit and therefore may be a feasible method of tissue protection in this setting.

This article has been cited by other articles:

				N. D. Vaziri and X. J. Zhou Potential mechanisms of adverse outcomes in trials of anemia correction with erythropoietin in chronic kidney disease Nephrol. Dial. Transplant., November 5, 2008; (2008) gfn601v1. [Full Text] [PDF]

				K.-U. Eckardt Erythropoietin and microvascular diabetic complications Nephrol. Dial. Transplant., October 24, 2008; (2008) gfn590v1. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673