Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles Elicit Better Preservation of the Intra-Renal Microvasculature Than Renal Revascularization in Pigs with Renovascular Disease.

Christopher M Ferguson,Kyra L Jordan,Rahele A Farahani,Amir Lerman,Alfonso Eirin,Xiang-Yang Zhu,Hui Tang,Lilach O Lerman,Ishran M Saadiq

doi:10.3390/cells10040763

Christopher M Ferguson, Kyra L Jordan + Show 7 more

Open Access

https://doi.org/10.3390/cells10040763

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Journal: Cells	Publication Date: Mar 31, 2021
Citations: 9	License type: CC BY 4.0

Affiliation: Mayo Clinic

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

Introduction

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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