Abstract
Background: Percutaneous transluminal renal angioplasty (PTRA) confers clinical and mortality benefits in select ‘high-risk’ patients with renovascular disease (RVD). Intra-renal-delivered extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) protect the kidney in experimental RVD, but have not been compared side-by-side to clinically applied interventions, such as PTRA. We hypothesized that MSC-derived EVs can comparably protect the post-stenotic kidney via direct tissue effects. Methods: Five groups of pigs (n = 6 each) were studied after 16 weeks of RVD, RVD treated 4 weeks earlier with either PTRA or MSC-derived EVs, and normal controls. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multi-detector CT, and renal microvascular architecture (3D micro CT) and injury pathways ex vivo. Results: Despite sustained hypertension, EVs conferred greater improvement of intra-renal microvascular and peritubular capillary density compared to PTRA, associated with attenuation of renal inflammation, oxidative stress, and tubulo-interstitial fibrosis. Nevertheless, stenotic kidney RBF and GFR similarly rose in both PTRA- and EV-treated pigs compared RVD + Sham. mRNA sequencing reveled that EVs were enriched with pro-angiogenic, anti-inflammatory, and antioxidants genes. Conclusion: MSC-derived EVs elicit a better preservation of the stenotic kidney microvasculature and greater attenuation of renal injury and fibrosis compared to PTRA, possibly partly attributed to their cargo of vasculo-protective genes. Yet, both strategies similarly improve renal hemodynamics and function. These observations shed light on diverse mechanisms implicated in improvement of post-stenotic kidney function and position EVs as a promising therapeutic intervention in RVD.
Highlights
Atherosclerotic renovascular disease (RVD) remains an important cause of secondary hypertension and renal failure that affects almost 7% of individuals older than 65 years old [1]
Diastolic, and mean arterial pressure that increased in RVD + Sham compared to Control decreased in RVD + Percutaneous transluminal renal angioplasty (PTRA), but remained elevated in RVD + extracellular vesicles (EVs) pigs (p = 0.20 vs. RVD + Sham)
Circulating isoprostane levels were elevated in RVD + Sham and RVD + PTRA compared to Control, but decreased in RVD pigs treated with EVs
Summary
Atherosclerotic renovascular disease (RVD) remains an important cause of secondary hypertension and renal failure that affects almost 7% of individuals older than 65 years old [1]. Several mechanisms are responsible for kidney injury distal to a stenosis, including oxidative stress, inflammation, defective angiogenesis, microvascular loss, and fibrosis [3] Each of these injurious pathways contributes, to some degree, to functional deterioration in the post-stenotic kidney, and are likely to represent potential therapeutic targets to preserve the ischemic kidney in RVD. Conclusion: MSC-derived EVs elicit a better preservation of the stenotic kidney microvasculature and greater attenuation of renal injury and fibrosis compared to PTRA, possibly partly attributed to their cargo of vasculo-protective genes. Both strategies improve renal hemodynamics and function.
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