Renovascular Disease and Mitochondrial Dysfunction in Human Mesenchymal Stem Cells.

Abstract

Renovascular disease impairs the capacity of human adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic murine kidneys. miR-378h modulated the capacity of renovascular disease adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic kidneys <i>in vivo</i>. Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue–derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. MSCs were harvested from subcutaneous abdominal fat of patients with renovascular disease and healthy volunteers (<i>n</i>=3 each), characterized and subsequently injected (5×10⁵/200 <i>μ</i>l) into mice 2 weeks after renal artery stenosis or sham surgery (<i>n</i>=6/group). Two weeks later, mice underwent imaging and tissue studies. MSCs from healthy volunteers and in those with renovascular disease were also characterized by mRNA/microRNA (miRNA) sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed <i>in vitro</i> before and after miRNA modulation and <i>in vivo</i> in additional renal artery stenosis mice administered with MSCs from renovascular disease pretreated with miR-378h mimic (<i>n</i>=5) or inhibitor (<i>n</i>=4). MSCs engrafted in stenotic mouse kidneys. Healthy volunteer MSCs (but not renovascular disease MSCs) decreased BP, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease MSCs versus healthy volunteer MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both <i>in vivo</i> and <i>in vitro</i> improved after miR-378h inhibition. Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_08_21_ASN0000000000000440.mp3