Abstract
IntroductionPathophysiological changes associated with chronic kidney disease impair angiogenic processes and increase renal fibrosis. Progenitor-like cells derived from adult kidney have been previously used to promote regeneration in acute kidney injury, even though it remained unclear whether the cells could be beneficial in chronic kidney disease (CKD).MethodsIn this study, we established a CKD model by five-sixths nephrectomy and mouse kidney progenitor-like cells (MKPCs) were intravenously administered weekly for 5 weeks after establishing CKD. We examined the impact of MKPCs on the progression of renal fibrosis and the potential of MKPCs to preserve the angiogenic process and prevent endothelial mesenchymal transition in vivo and in vitro.ResultsOur results demonstrate that the MKPCs delayed interstitial fibrosis and the progression of glomerular sclerosis and ameliorated the decline of kidney function. At 17 weeks, the treated mice exhibited lower blood pressures, higher hematocrit levels, and larger kidney sizes than the control mice. In addition, the MKPC treatment prolonged the survival of the mice with chronic kidney injuries. We observed a decreased recruitment of macrophages and myofibroblasts in the interstitium and the increased tubular proliferation. Notably, MKPC both decreased the level of vascular rarefaction and prevented endothelial mesenchymal transition (EndoMT) in the remnant kidneys. Moreover, the conditioned medium from the MKPCs ameliorated endothelial cell death under hypoxic culture conditions and prevented TGF-β-induced EndoMT through downregulation of phosphorylated Smad 3 in vitro.ConclusionsMKPCs may be a beneficial treatment for kidney diseases characterized by progressive renal fibrosis. The enhanced preservation of angiogenic processes following MKPC injections may be associated with decreased fibrosis in the remnant kidney. These findings provide further understanding of the mechanisms involved in these processes and will help develop new cell-based therapeutic strategies for regenerative medicine in renal fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0241-8) contains supplementary material, which is available to authorized users.
Highlights
Pathophysiological changes associated with chronic kidney disease impair angiogenic processes and increase renal fibrosis
We provide evidence that the antifibrotic activity of Mouse kidney progenitor-like cell (MKPC) is mediated by a novel endocrine mechanism of action, demonstrating that conditioned medium derived from MKPCs inhibits transforming growth factor beta (TGF-β)-induced endothelial–mesenchymal transition (EndoMT) in vitro
We further demonstrate the relevance of these findings in vivo, showing that intravenous administration of MKPCs could protect five-sixths nephrectomized mice from renal fibrosis via preservation of angiogenic processes
Summary
Pathophysiological changes associated with chronic kidney disease impair angiogenic processes and increase renal fibrosis. Progenitor-like cells derived from adult kidney have been previously used to promote regeneration in acute kidney injury, even though it remained unclear whether the cells could be beneficial in chronic kidney disease (CKD). The therapeutic strategy for slowing the renal progression of CKD involves controlling blood pressure, using angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers, and restricting protein [2]. The effects of these modalities remain insufficient, and in most cases CKD leads to ESRD. The important challenge of clinical translation is the risk for long-term maldifferentiation This leads to the necessity of applying progenitor or stem cells that are derived from kidney to treat chronic kidney injury
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