Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice.

Abstract

Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, serelaxin (RLX), enhanced BM-MSC-induced renoprotection in preclinical CKD models. Given the increased interest and manufacturing advantages to using stem cell-derived exosomes (EXO) as therapeutics, this study determined whether RLX could enhance the therapeutic efficacy of BM-MSC-EXO, and compared the renoprotective effects of RLX and BM-MSC-EXO versus RLX and BM-MSCs in mice with hypertensive CKD. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and given saline to drink (1K/DOCA/salt) for 21 days. Control mice were uninephrectomised and given normal drinking water for the same time-period. Subgroups of 1K/DOCA/salt-hypertensive mice were then treated with either RLX (0.5 mg/kg/day) or BM-MSC-EXO (25 μg/mouse; equivalent to 1-2 × 106 BM-MSCs/mouse) alone; combinations of RLX and BM-MSC-EXO or BM-MSCs (1 × 106/mouse); or the mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day), from days 14-21. 1K/DOCA/salt-hypertensive mice developed kidney tubular damage, inflammation and fibrosis, and impaired kidney function 21 days post-injury. Whilst RLX alone attenuated the 1K/DOCA/salt-induced fibrosis, BM-MSC-EXO alone only diminished measures of tissue inflammation post-treatment. Comparatively, the combined effects of RLX and BM-MSC-EXO or BM-MSCs demonstrated similar anti-fibrotic efficacy, but RLX and BM-MSCs offered broader renoprotection over RLX and/or BM-MSC-EXO, and comparable effects to spironolactone. Only RLX and BM-MSCs, but not RLX and/or BM-MSC-EXO, also attenuated the 1K/DOCA/salt-induced hypertension. Hence, although RLX improved the renoprotective effects of BM-MSC-EXO, combining RLX with BM-MSCs provided a better therapeutic option for hypertensive CKD.

• Authors: Yifang Li, Amlan Chakraborty, Brad R S Broughton, Dorota Ferens, Robert E Widdop, Sharon D Ricardo, Chrishan S Samuel
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 144 Pg. 112256 (Dec 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 34607108 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Antifibrotic Agents
• Antihypertensive Agents
• Mineralocorticoid Receptor Antagonists
• Recombinant Proteins
• Sodium Chloride, Dietary
• serelaxin protein, human
• Spironolactone
• Desoxycorticosterone Acetate
• Relaxin

Topics

• Animals
• Antifibrotic Agents (pharmacology)
• Antihypertensive Agents (pharmacology)
• Blood Pressure (drug effects)
• Cells, Cultured
• Combined Modality Therapy
• Desoxycorticosterone Acetate
• Disease Models, Animal
• Exosomes (metabolism, transplantation)
• Fibrosis
• Hypertension (metabolism, pathology, physiopathology, therapy)
• Kidney (drug effects, metabolism, pathology)
• Macrophages (drug effects, metabolism)
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism)
• Mice, Inbred C57BL
• Mineralocorticoid Receptor Antagonists (pharmacology)
• Nephrectomy
• Recombinant Proteins (pharmacology)
• Relaxin (pharmacology)
• Renal Insufficiency, Chronic (metabolism, pathology, physiopathology, prevention & control)
• Sodium Chloride, Dietary
• Spironolactone (pharmacology)
• T-Lymphocytes (drug effects, metabolism)
• Mice