Improving Treatment Options in Atherosclerotic Renal Artery Stenosis (ARAS)
Renal artery stenosis is most commonly caused by atherosclerosis. People with atherosclerotic renal artery stenosis (ARAS), also called renovascular disease, have an increased risk of developing cardiovascular disease and end-stage renal failure.
A common intervention for people with ARAS is the restoration of vessel patency by revascularization. But the procedure's ability to restore renal function and improve blood pressure control is still controversial.
Therefore, strategies to more effectively preserve kidney function distal to the stenosis are urgently needed.
Our research team has been engaged in clarifying mechanisms of renal injury in ARAS for three decades. We recently focused on strategies to improve the response to revascularization.
We also developed and characterized a novel animal model of ARAS and unique physiological imaging techniques that allow study of the single-kidney function and structure, both in vivo and in vitro. Our team also has explored the effects of obesity and metabolic syndrome on renal injury in renal artery stenosis.
Our studies related to improving treatment in ARAS include:
- Cell-based therapy, including stem cells and stromal cells; stem cell derivatives, such as extracellular vesicles; and resident stem and progenitor cells.
- Mitochondria-related drugs.
- Growth factors.
- Senolytic drugs.
- Low-energy ultrasound shock wave therapy.
Stem cell therapy
Therapeutic use of progenitor cells and stem cells is becoming an attractive alternative to conventional treatments, especially for diseases that are refractory to other treatments.
Recent projects involved delivery of adipose tissue-derived mesenchymal stem cells (MSCs) into the stenotic kidney with or without concurrent revascularization to restore cellular integrity and decrease the progression to renal failure in animal models and in people with ARAS.
Our current projects involve delivery of MSCs in metabolic syndrome and characterization and delivery of MSC-derived membrane microparticles (extracellular vesicles, such as microvesicles and exosomes) using RNA-seq, proteomics and epigenetic approaches.
Mitochondria-related drugs
One of the potential underlying causes of the failure of revascularization to restore renal function is mitochondrial damage. MTP-131 (bendavia, elamipretide) is a novel compound that targets the mitochondria to stabilize cardiolipin, improve energy utilization and attenuate apoptosis associated with cardiovascular insults.
Our research evaluated the potential effects of intrarenal infusion of bendavia to improve renal function in the kidneys of people and animal models with ARAS.
Current projects are evaluating the structure and function of MSC mitochondria and circulating levels of mitochondria-derived peptides in people with obesity or renovascular dysfunction. We're also studying their role in regulating MSC function in people.
Senolytic drugs
Cellular senescence is a cellular program characterized by a permanent cell-cycle arrest that eventually alters cell function. Cellular senescence leads cells to acquire a senescence-associated secretory phenotype (SASP), a secretome comprised of cytokines, chemokines and growth factors. Aberrant and chronic accumulation of senescent cells harboring the SASP phenotype can exert noxious effects on neighboring cells and drive feed-forward premature aging and tissue injury.
Senolytic compounds target prosurvival pathways in senescent cells and thereby facilitate their elimination.
Our research is evaluating the role of cellular senescence in driving renal and cardiac injury and the potential beneficial effects of senolytic drugs.
Project contact
For more information about this project, email Alfonso Eirin Massat, M.D.