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Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease

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Abstract

Extracellular vesicles (EVs) deliver genes and proteins to recipient cells, and mediate paracrine actions of their parent cells. Intrarenal delivery of mesenchymal stem cell (MSC)-derived EVs preserves stenotic-kidney function and reduces release of pro-inflammatory cytokines in a swine model of coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS). We hypothesized that this approach is also capable of blunting cardiac injury and dysfunction. Five groups of pigs were studied after 16 weeks of diet-induced MetS and RAS (MetS + RAS), MetS and MetS + RAS treated 4 weeks earlier with a single intrarenal delivery of EVs-rich fraction harvested from autologous adipose tissue-derived MSCs, and lean and MetS Shams. Cardiac structure, function, and myocardial oxygenation were assessed in vivo using imaging, and cardiac inflammation, senescence, and fibrosis ex vivo. Inflammatory cytokine levels were measured in circulating and renal vein blood. Intrarenal EV delivery improved stenotic-kidney glomerular filtration rate and renal blood flow, and decreased renal release of monocyte-chemoattractant protein-1 and interleukin-6. Furthermore, despite unchanged systemic hemodynamics, intrarenal EV delivery in MetS + RAS normalized cardiac diastolic function, attenuated left ventricular remodeling, cellular senescence and inflammation, and improved myocardial oxygenation and capillary density in MetS + RAS. Intrarenal delivery of MSC-derived EVs blunts myocardial injury in experimental MetS + RAS, possibly related to improvement in renal function and systemic inflammatory profile. These observations underscore the central role of inflammation in the crosstalk between the kidney and heart, and the important contribution of renal function to cardiac structural and functional integrity in coexisting MetS and RAS.

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Funding

This study was partly supported by NIH Grant Numbers: DK120292, DK104273, HL123160, and DK102325, and DK106427.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, 55905, USA

    Lei Zhang, Xiang-Yang Zhu, Yu Zhao, Alfonso Eirin, Lei Liu, Christopher M. Ferguson, Hui Tang & Lilach O. Lerman

  2. Department of Urology, Zhongda Hospital, Southeast University, Nanjing, 210009, People’s Republic of China

    Lei Zhang

  3. Department of Internal Medicine, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China

    Yu Zhao & Lei Liu

  4. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, 55905, USA

    Amir Lerman & Lilach O. Lerman

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Dr. Lerman receives grant funding from Novo Nordisk, and is an advisor to Weijian Technologies and AstraZeneca. All the other authors declare that they have no conflict of interest.

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Zhang, L., Zhu, XY., Zhao, Y. et al. Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease. Basic Res Cardiol 115, 16 (2020). https://doi.org/10.1007/s00395-019-0772-8

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