A mitochondrial permeability transition pore inhibitor improves renal outcomes after revascularization in experimental atherosclerotic renal artery stenosis

Alfonso Eirin, Zilun Li, Xin Zhang, James D. Krier, John R. Woollard, Xiang Yang Zhu, Hui Tang, Sandra M. Herrmann, Amir Lerman, Stephen C. Textor, Lilach O. Lerman

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1242-1249
Number of pages8
JournalHypertension
Volume60
Issue number5
DOIs
StatePublished - Nov 2012

Keywords

  • Bendavia
  • oxidative stress
  • renovascular hypertension
  • reperfusion injury
  • revascularization

ASJC Scopus subject areas

  • Internal Medicine

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