Abstract
Background Coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS) are linked to poor renal outcomes. Mesenchymal stem/stromal cell- (MSC-) derived extracellular vesicles (EVs) from lean animals show superior ability to repair the experimental MetS+RAS kidney compared to EVs from MetS pig MSCs. We hypothesized that MetS leads to selective packaging in porcine EVs of microRNAs capable of targeting mitochondrial genes, interfering with their capacity to repair the MetS+RAS kidney. Methods Five groups of pigs (n = 7 each) were studied after 16 weeks of diet-induced MetS and RAS (MetS+RAS) and MetS+RAS 4 weeks after a single intrarenal delivery of EVs harvested from allogeneic adipose tissue-derived MSCs isolated from Lean or MetS pigs, and Lean or MetS sham controls. Single-kidney blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector CT, whereas EV microRNA cargo, renal tubular mitochondrial structure and bioenergetics, and renal injury pathways were assessed ex vivo. Results microRNA sequencing revealed 19 dysregulated microRNAs capable of targeting several mitochondrial genes in MetS-EVs versus Lean-EVs. Lean- and MetS-EVs were detected in the stenotic kidney 4 weeks after administration. However, only MetS-EVs failed to improve renal mitochondrial density, structure, and function or attenuate oxidative stress, tubular injury, and fibrosis. Furthermore, Lean-EVs but not MetS-EVs restored RBF and GFR in MetS+RAS. Conclusion MetS alters the cargo of mitochondria-related microRNAs in swine MSC-derived EVs, which might impair their capacity to repair the poststenotic kidney in MetS+RAS. These observations may contribute to develop approaches to improve the efficacy of MSC-EVs for patients with MetS.
Highlights
Renal artery stenosis (RAS) is becoming more frequently identified in patients with chronic kidney disease and may affect almost 7% of adults older than 65 [1] and more than 50% of patients with diffuse atherosclerosis [2]
Fasting glucose levels were similar among the groups, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels were comparably higher in all metabolic syndrome (MetS) groups, indicating early prediabetic MetS [24]
We compared the miRNA content of Lean- and MetS-extracellular vesicles (EVs) using miRNA sequencing analysis, which identified 11 miRNAs upregulated and 8 miRNAs downregulated in MetS-EVs versus Lean-EVs (Figure 2(a)). quantitative polymerase chain reaction (qPCR) analysis revealed that the expression of randomly selected differentially expressed candidate miRNAs agreed with miRNA-seq analysis, with miR196a and miR-132 upregulated and miR-192 and miR-320 downregulated in MetS-EVs (Figure 2(b))
Summary
Renal artery stenosis (RAS) is becoming more frequently identified in patients with chronic kidney disease and may affect almost 7% of adults older than 65 [1] and more than 50% of patients with diffuse atherosclerosis [2]. Adipose tissue-derived mesenchymal stem/stromal cells (MSCs) have demonstrated important regenerative properties in both experimental [4, 5] and clinical [6, 7] RAS. These cells produce substantial amounts of extracellular vesicles (EVs), which carry genetic and protein material capable of. MetS alters the cargo of mitochondria-related microRNAs in swine MSCderived EVs, which might impair their capacity to repair the poststenotic kidney in MetS+RAS
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