Abstract
Scattered tubular-like cells (STCs) are renal tubular cells that survive episodes of renal injury and acquire progenitor-like characteristics to repair other damaged kidney cells. STCs release proangiogenic factors in culture and induce microvascular proliferation in injured murine kidneys in vivo. Renovascular disease (RVD) compromises the reparative capacity of STCs, but the underlying mechanisms remain unknown. We hypothesized that RVD alters the expression of vasculature-related genes in swine STCs and impair their vasculoprotective properties. CD24(+)/CD133(+) STCs were harvested from female pig kidneys after 10 wk of RVD or sham (n = 6 each), and the mRNA profiles of vasculature-related genes were analyzed using mRNA and microRNA seq (n = 3/group). STC expression of candidate differentially expressed (DE) genes and their capacity to induce human umbilical endothelial cells (HUVECs) to form tube-like networks were subsequently assessed in vitro before and after micro-RNA (miRNA) modulation (n = 6 each). mRNA-seq identified 67 upregulated and 42 downregulated vasculature-related genes in RVD-STCs. Four miRNAs were upregulated and 12 downregulated in RVD-STCs and found to target 31.3% to 40.5% of DE vasculature-related genes. Modulation in vitro of representative miRNAs decreased RVD-STC expression of anti-angiogenic and increased expression of proangiogenic target genes, respectively. Furthermore, this restored the ability of STCs to induce HUVEC tube formation on Matrigel that was impaired in RVD. Chronic renal ischemia alters the expression of vasculature-related genes in swine STCs, likely through posttranscriptional mechanisms, impairing their proangiogenic activity. These observations may contribute to develop novel approaches to preserve the reparative capacity of STCs in individuals with RVD.NEW & NOTEWORTHY The intrinsic reparative capacity of the adult mammalian kidney is restricted to the ability of scattered tubular-like cells (STCs) to repair damaged kidney cells. Our study provides evidence that chronic renal ischemia alters the mRNA/miRNA profile of angiogenic/vascular development genes of swine STCs, limiting their potential to repair injured tubular cells. Our observations may assist in developing new therapies to improve renal repair in individuals with chronic renal ischemia.