Kidney fibroblasts but not pericytes are involved in fibrogenic and cell plasticity changes that lead to long-term kidney fibrosis and kidney dysfunction associated to dysfunctional telomeres [2021]
Tubulointerstitial fibrosis associated to chronic kidney disease represents a global healthcare problem. We showed previously that short and dysfunctional telomeres lead to interstitial renal fibrosis, however, the cell-of-origin of kidney fibrosis associated to telomere dysfunction was unknown to date. To identify the specific cell type responsible for this type of renal fibrosis, we induced telomere dysfunction by deleting the Trf1 telomere-binding factor both in renal fibroblasts and pericytes both in short-term and long-term life-long experiments in mice. Short-term Trf1 deletion in renal fibroblasts and pericytes was not sufficient to trigger kidney fibrosis. However, long-term persistent deletion of Trf1 in fibroblasts, triggered inflammation, cell cycle arrest, fibrogenesis, and vascular rarefaction. These cellular responses lead to macrophage-to-myofibroblast transition (MMT), Endothelial-to-mesenchymal transition (EndMT), and epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at humane-endpoint when deletion of Trf1 in fibroblasts was maintained throughout the lifespan of mice. In contrast, Trf1 deletion in pericytes did not lead to any kidney phenotypes both in short-term and long-term experiments. Overall design: Tamoxifen (TMX) (Sigma Aldrich, T-5648-1G) was intraperitoneally (i.p.) injected to six-to eight-week-old male and female Trf1+/+ KFP+/t Cre+/t and Trf1lox/lox KFP+/t Cre+/t mice for three times a week for 8 weeks. Fibroblasts were isolated.