Abstract
Renal interstitial fibrosis is characterized by the development of myofibroblasts, originating from resident renal and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various factors. Among these, endothelins have been discussed as potential modulators of renal fibrosis. Utilizing mouse models of adenine nephropathy (AN) and unilateral ureter occlusion (UUO), this study aimed to investigate the contribution of endothelin signaling in stromal mesenchymal resident renal interstitial cells. We found in controls that adenine feeding and UUO caused marked upregulations of endothelin-1 (ET-1) gene expression in endothelial and in tubular cells and a strong upregulation of ETA-receptor (ETA-R) gene expression in interstitial and mesangial cells, while the gene expression of ETB-receptor (ETB-R) did not change. Conditional deletion of ETA-R and ETB-R gene expression in the FoxD1 stromal cell compartment which includes interstitial cells significantly reduced renal ETA-R gene expression and moderately lowered renal ETB-R gene expression. ET receptor (ET-R) deletion exerted no apparent effects on kidney development nor on kidney function. Adenine feeding and UUO led to similar increases in profibrotic and proinflammatory gene expression in control as well as in ETAflflETBflfl FoxD1Cre+ mice (ET-Ko). In summary, our findings suggest that adenine feeding and UUO activate endothelin signaling in interstitial cells which is due to upregulated ETA-R expression and enhanced renal ET-1 production Our data also suggest that the activation of endothelin signaling in interstitial cells has less impact for the development of experimentally induced fibrosis.
Highlights
Development and progression of renal fibrosis is a characteristic of chronic kidney disease and is widely believed as the consequence of an excess accumulation of extracellular matrix (ECM) proteins such as collagens, fibronectin, or tenascins [7, 27, 46, 55]
We found that adenine-induced nephropathy and unilateral ureter occlusion led to an upregulation of mainly tubular ET-1 expression and to an upregulation of ETA gene expression in the stromal cell compartment which includes interstitial cells
Our findings of an activation of the endothelin system in fibrotic kidney disease is in accordance with previous reports, which demonstrated either an enhanced ET-1 gene expression [1, 16, 43, 44] or an increased ETA gene expression [9, 16] in experimentally induced kidney fibrosis
Summary
Development and progression of renal fibrosis is a characteristic of chronic kidney disease and is widely believed as the consequence of an excess accumulation of extracellular matrix (ECM) proteins such as collagens, fibronectin, or tenascins [7, 27, 46, 55]. It is well established that myofibroblasts are the key mediators of fibrosis by serving as the primary matrix/collagen-producing cells. These myofibroblasts transdifferentiate from several cell types including fibroblasts, pericytes, monocytes, tubular, and. Among a variety of cytokines and signaling factors involved in myofibroblast formation and the progression of fibrosis, the role of ET-1 has been studied in various experimental models [2, 5, 45, 48]. An important role of ET-1 in renal fibrosis was elucidated from the finding that transgenic mice overexpressing human ET-1 develop renal abnormalities associated with interstitial fibrosis [25] and that
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