A Mitochondrial Permeability Transition Pore Inhibitor Improves Renal Outcomes After Revascularization in Experimental Atherosclerotic Renal Artery Stenosis
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- Alfonso Eirin
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Zilun Li
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Xin Zhang
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- James D. Krier
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- John R. Woollard
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Xiang-Yang Zhu
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Hui Tang
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Sandra M. Herrmann
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Amir Lerman
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Stephen C. Textor
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
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- Lilach O. Lerman
- From the Divisions of Nephrology and Hypertension (A.E., Z.L., X.Z., J.D.K., J.R.W., X.-Y.Z., H.T., S.M.H., S.C.T., L.O.L.) and Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; Division of Vascular Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Z.L.).
説明
<jats:p>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.</jats:p>
収録刊行物
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- Hypertension
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Hypertension 60 (5), 1242-1249, 2012-11
Ovid Technologies (Wolters Kluwer Health)