A Mitochondrial Permeability Transition Pore Inhibitor Improves Renal Outcomes After Revascularization in Experimental Atherosclerotic Renal Artery Stenosis

Abstract

Revascularization improves blood pressure but not renal function in most patients with atherosclerotic renal artery stenosis (ARAS), possibly related to injury incurred during renal reperfusion. Bendavia, a novel tetrapeptide that inhibits mitochondrial permeability transition pore opening, reduces apoptosis, oxidative stress, and ischemia-reperfusion injury in experimental models. However, its potential for improving renal response to revascularization of chronic ARAS is unknown. We hypothesized that adjunct Bendavia would improve renal structure and function after percutaneous transluminal renal angioplasty (PTRA). Pigs were treated after 6 weeks of ARAS or control with PTRA+stenting (or sham), adjunct continuous 4-hour infusion of Bendavia (0.05 mg/kg IV) or vehicle (n=7 each) during PTRA. Single-kidney renal blood flow and glomerular filtration rate were studied 4 weeks later and renal mitochondrial biogenesis, microvascular architecture, and injurious pathways evaluated ex vivo. Monocyte chemoattractant protein-1 levels rose after PTRA, suggesting inflammatory injury. Bendavia did not immediately affect inflammatory cytokine levels, yet 4 weeks later, stenotic kidney renal blood flow and glomerular filtration rate both improved (44.00 ± 0.21% and 36.40 ± 10.21%, respectively) in ARAS+PTRA+Bendavia compared with ARAS+PTRA+vehicle. Renal mitochondrial biogenesis was restored after PTRA+Bendavia, and microvascular rarefaction, apoptosis, oxidative stress, tubular injury, and fibrosis decreased. Infusion of Bendavia during PTRA preserved mitochondrial biogenesis, renal hemodynamics, and function, and attenuated tissue injury in swine ARAS. Thus, functional mitochondrial injury during renal reperfusion may sustain renal inflammatory injury and limit kidney recovery after PTRA. Potent antiapoptotic and antioxidant effects provide Bendavia a novel therapeutic potential for improving kidney outcomes after PTRA in experimental ARAS.

Revascularization in Experimental Atherosclerotic Renal Artery Stenosis: Role of Mitochondrial Targeted Peptides (Bendavia)

“…Similarly, Mizuguchi et al demonstrated that pretreatment of rats with Bendavia decreased renal damage and oxidative stress in a model of unilateral ureteral obstruction [19]. In line with these observations, we have recently shown in swine ARAS that systemic infusion of Bendavia during the PTRS procedure (from 30min before to 3.5 hours after PTRS), promoted renal mitochondrial biogenesis and attenuated microvascular remodeling, apoptosis, oxidative stress, tubular damage, and fibrosis evaluated four weeks after revascularization [20]. Furthermore, renal inflammation, one of the main determinants of disease progression and response to revascularization in ARAS [21], was restored to normal levels in Bendavia-treated pigs.…”

The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

“…9,[40][41][42][43][44] Although it was known that SS-31 concentrates in the IMM and inhibits MPT, 10 its exact mechanism of action remained unclear. Because SS-31 carries a 3+ net charge, we hypothesized that it binds to the anionic phospholipid CL that is uniquely expressed on the IMM.…”

“…41 SS-31 can even improve kidney outcome after reperfusion after chronic ischemia in a porcine model of renal artery stenosis. 44 The validity of CL as a target for therapeutic development is currently being evaluated in a multinational clinical trial with Bendavia for reperfusion injury in patients with acute coronary events (NCT01572909), and a Phase 2 trial was just initiated to assess the effectiveness of Bendavia on improving renal function after angioplasty for severe renal artery stenosis (NCT01755858). …”

Paradigm Shifts in Atherosclerotic Renovascular Disease

“…49 Intravenous administration of a mitochondrial-targeted peptide (SS31, Bendavia; Stealth Biopharmaceuticals, Boston, MA) during renal artery angioplasty in a swine model restored measures of mitochondrial biogenesis and limited vascular rarefication, apoptosis, oxidative stress, and fibrosis. 50 Remarkably, blood flow and GFR in the treated animals were restored to control levels, suggesting that sustained mitochondrial dysfunction may severely limit the potential benefits of restoring renal blood flow. Mitochondrial swelling and distortion are among the earliest histologic changes observed in temporary renal artery clamping in humans.…”