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J. Clin. Med. 2018, 7(2), 15; https://doi.org/10.3390/jcm7020015

CERA Attenuates Kidney Fibrogenesis in the db/db Mouse by Influencing the Renal Myofibroblast Generation

1
Department of Internal Medicine III, University Hospital Jena, Am Klinikum 1, D-07747 Jena, Germany
2
Institute of Medical Genetics and Applied Genomics, University Tübingen, Calwerstraße 7, D-72076 Tübingen, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 5 January 2018 / Revised: 24 January 2018 / Accepted: 24 January 2018 / Published: 30 January 2018
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Abstract

Tubulointerstitial fibrosis (TIF) is a pivotal pathophysiological process in patients with diabetic nephropathy (DN). Multiple profibrotic factors and cell types, including transforming growth factor beta 1 (TGF-β1) and interstitial myofibroblasts, respectively, are responsible for the accumulation of extracellular matrix in the kidney. Matrix-producing myofibroblasts can originate from different sources and different mechanisms are involved in the activation process of the myofibroblasts in the fibrotic kidney. In this study, 16-week-old db/db mice, a model for type 2 DN, were treated for two weeks with continuous erythropoietin receptor activator (CERA), a synthetic erythropoietin variant with possible non-hematopoietic, tissue-protective effects. Non-diabetic and diabetic mice treated with placebo were used as controls. The effects of CERA on tubulointerstitial fibrosis (TIF) as well as on the generation of the matrix-producing myofibroblasts were evaluated by morphological, immunohistochemical, and molecular biological methods. The placebo-treated diabetic mice showed significant signs of beginning renal TIF (shown by picrosirius red staining; increased connective tissue growth factor (CTGF), fibronectin and collagen I deposition; upregulated KIM1 expression) together with an increased number of interstitial myofibroblasts (shown by different mesenchymal markers), while kidneys from diabetic mice treated with CERA revealed less TIF and fewer myofibroblasts. The mechanisms, in which CERA acts as an anti-fibrotic agent/drug, seem to be multifaceted: first, CERA inhibits the generation of matrix-producing myofibroblasts and second, CERA increases the ability for tissue repair. Many of these CERA effects can be explained by the finding that CERA inhibits the renal expression of the cytokine TGF-β1. View Full-Text
Keywords: diabetic nephropathy; DN; erythropoietin; EPO; CERA; tubulointerstitial fibrosis; TIF; myofibroblast; type 2 diabetes; db/db mouse diabetic nephropathy; DN; erythropoietin; EPO; CERA; tubulointerstitial fibrosis; TIF; myofibroblast; type 2 diabetes; db/db mouse
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Fischer, C.; Deininger, N.; Wolf, G.; Loeffler, I. CERA Attenuates Kidney Fibrogenesis in the db/db Mouse by Influencing the Renal Myofibroblast Generation. J. Clin. Med. 2018, 7, 15.

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