Renovascular disease (RVD) produces chronic underperfusion of the renal parenchyma and progressive ischemic injury. Metabolic abnormalities often accompany renal ischemia, and are linked to poorer renal outcomes. However, the mechanisms of injury in kidneys exposed to the ischemic and metabolic components of RVD are incompletely understood. We hypothesized that coexisting renal artery stenosis (RAS) and metabolic syndrome (MetS) would exacerbate mitochondrial damage, aggravating poststenotic kidney injury in swine.
Domestic pigs were studied after 16 weeks of either standard diet (Lean) or high-fat/high-fructose (MetS) with or without superimposed RAS (n = 6 each). Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector-CT, and renal tubular mitochondrial structure, homeostasis and function and renal injury ex vivo.
Both RAS groups achieved significant stenosis. Single-kidney RBF and GFR were higher in MetS compared with Lean, but decreased in Lean+RAS and MetS+RAS vs. their respective controls. MetS and RAS further induced changes in mitochondrial structure, dynamics, and function, and their interaction (diet × ischemia) decreased matrix density, mitophagy, and ATP production, and lead to greater renal fibrosis.
Coexisting RAS and MetS synergistically aggravate mitochondrial structural damage and dysfunction, which may contribute to structural injury and dysfunction in the poststenotic kidney. These observations suggest that mitochondrial damage precedes loss of renal function in experimental RVD, and position mitochondria as novel therapeutic targets in these patients.
aDivision of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
bDepartment of Nephrology, the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
Correspondence to Alfonso Eirin, MD, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 507 538 9941; fax: +1 507 266 9316; e-mail: firstname.lastname@example.org
Abbreviations: ACR, albumin creatinine ratio; ANOVA, analysis of variance; ATP, adenosine triphosphate; BNIP, BCL2 interacting protein; COX, cytochrome-c oxidase; DHE, dihydroethidium; DRP, dynamin-related protein; GFR, glomerular filtration rate; H2O2, hydrogen peroxide; HOMA-IR, homeostasis model assessment of insulin resistance; MDCT, multi-detector computed tomography; MetS, metabolic syndrome; MFN, mitofusin; PGC, peroxisome proliferator-activated receptor-γ-coactivator; PRA, plasma renin activity; RAS, renal artery stenosis; RBF, renal blood flow; ROS, reactive oxygen species; RVD, renovascular disease; TOM, translocases of the outer membrane
Received 8 November, 2018
Revised 21 March, 2019
Accepted 25 March, 2019
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