Mitoprotection preserves the renal vasculature in porcine metabolic syndrome

Abstract

The metabolic syndrome (MetS) induces intrarenal microvascular disease, which may involve mitochondrial injury. The mitochondrial cardiolipin-targeting peptide elamipretide (ELAM) improves the microcirculation in post-stenotic kidneys, but its ability to attenuate MetS-induced renal vascular damage is unknown. We hypothesized that chronic treatment with ELAM would decrease renal vascular remodelling and function in swine MetS. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with daily injections of ELAM (0.1 mg kg ), and lean control (Lean) animals (n = 6 each). Single-kidney regional perfusion, blood flow and glomerular filtration rate were measured with multi-detector computed tomography (CT). Peritubular capillary (PTC) endothelial cell (EC) mitochondrial density and cardiolipin content were assessed in situ, as were PTC-EC apoptosis and oxidative stress. The spatial density of PTCs (Haematoxylin and Eosin staining) and renal microvessels (micro-CT), and renal artery endothelial function (organ bath) were characterized. Regional perfusion and serum creatinine were preserved in MetS pigs, but renal blood flow and glomerular filtration rate were higher compared with Lean. Mitochondrial density and cardiolipin content were diminished in MetS PTC-ECs, but improved in ELAM-treated pigs, as did PTC density. Elamipretide also attenuated PTC-EC oxidative stress and apoptosis. Furthermore, ELAM improved renal microvascular density, decreased microvascular remodelling and restored endothelial nitric oxide expression and endothelium-dependent relaxation of renal artery segments. In conclusion, MetS-induced mitochondrial alterations might contribute to renal PTC and microvascular loss and might impair renal artery endothelial function in pigs. Mitoprotection with ELAM preserved a hierarchy of renal vessels, underscoring its potential to ameliorate renal vascular injury in MetS.

Enhancing Mitochondrial Health to Treat Hypertension

“…In line with this, we have shown that renovascular hypertension induced mitochondrial damage in renal tubular cells and cardiomyocytes in pigs, associated with renal and cardiac dysfunction [10–13]. Similarly, obesity-induced hypertension led to mitochondrial alterations in renal artery and coronary vessels that impaired microvascular endothelial function in pigs [14, 15]. Taken together, these studies underscore the contribution of dysfunctional mitochondria to the pathophysiology of hypertension-induced organ damage.…”

“…Contrarily, treatment with ELAM, which restored cardiolipin and preserved mitochondrial function in renal artery and coronary artery endothelial cells, did not affect blood pressure levels in either obesity-induced [14, 15] or renovascular hypertension [12]. Differences in the effect on blood pressure among different classes of mitochondria-targeted therapies likely reflect distinct mechanisms of actions, but justify further investigation.…”

“…Chronic treatment with ELAM has been shown to attenuate mitochondrial damage and ROS production in murine models of angiotensin-II-induced cardiac hypertrophy and pressure overload [24, 25]. In line with this, subcutaneous administration of ELAM for 4 weeks attenuated structural and functional changes that obesity-induced hypertension imposed in the renal medullary mitochondria [26] and renal vasculature [15]. Notably, the beneficial effects of ELAM in this model were extended to the heart where it preserved mitochondrial organization [27] and decreased myocardial vascular impairment [14].…”

“…Treatment with the mitochondria-targeted antioxidant mitoQ exerted important antiapoptotic properties in cardiomyocyte-like cells and isolated hearts [65], and improved mitochondrial dysfunction in heart failure induced by pressure overload [38]. Likewise, cardiolipin protection with ELAM attenuated renal and cardiac apoptosis in experimental renovascular [10–13] and obesity-induced [14, 15] hypertension, supporting the notion that mitochondria-targeted interventions may attenuate hypertension-related apoptosis.…”

Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets

“…In a rat renal ischemia/reperfusion model, ELAM protected tubular cells from oxidative damage accelerating post-reperfusion recovery [ 245 ]. Protection of mitochondria by ELAM restores cardiolipin content in renal endothelial cells by increasing their number, reducing vessel loss, and ameliorating renal perfusion in a porcine metabolic syndrome model [ 252 ]. Despite these pre-clinical promising results, clinical studies on humans reported conflicting results.…”