The Metabolic Syndrome Induces Early Changes in the Swine Renal Medullary Mitochondria

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 184; pp. 45 - 56.e9
• Main Authors: Eirin, Alfonso, MD, Woollard, John R, Ferguson, Christopher M, Jordan, Kyra L, Tang, Hui, MD, PhD, Textor, Stephen C., MD, Lerman, Amir, MD, Lerman, Lilach O., MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2017
• Subjects: Animals; Cardiolipins - metabolism; Diet - adverse effects; Female; Glomerular Filtration Rate; Internal Medicine; Kidney Medulla - diagnostic imaging; Kidney Medulla - drug effects; Kidney Medulla - pathology; Magnetic Resonance Imaging; Metabolic Syndrome - drug therapy; Metabolic Syndrome - etiology; Metabolic Syndrome - physiopathology; Mitochondria - drug effects; Mitochondria - pathology; Oligopeptides - pharmacology; Oxidative Stress - drug effects; Renal Circulation; Sus scrofa; OPA; plasma renin activity; DRP; PAS; PT; cardiolipin synthase; phosphate-buffered saline; dynamin-related protein; H2O2; Taz; mPTP; mitochondrial permeability transition pore; elamipretide; RVR; Mitochondria; TUNEL; Periodic acid-Schiff; PPAR; taffazin; cytochrome oxidase; blood oxygen level dependent magnetic resonance imaging; TRX; PBS; homeostasis model assessment of insulin resistance; glomerular filtration rate; hydrogen peroxide; lactate dehydrogenase; CRLS; renal vascular resistance; optic atrophy; HOMA-IR; MetS; ELAM; multi-detector computed tomography; superoxide dismutase; ROS; mTAL; DHE; thioredoxin; Metabolic syndrome; Kidney; LDH; GFR; reactive oxygen species; peroxisome proliferator-activated receptor; BOLD-MRI; proximal tubular; SOD; MDCT; COX; Ox-LDL; dihydroethidium; terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; Bax; Cardiolipin; medullary thick ascending limb; oxidized low-density lipoprotein; B-cell lymphoma (Bcl)-xl and Bcl2-associated X protein; PRA
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2017.03.002

Abstract The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by substrate excess, leading to inefficient energy production and thereby tissue hypoxia. Mitochondrial dysfunction is emerging as an important determinant of renal damage, but whether it contributes to MetS-induced renal injury remains unknown. We hypothesized that early MetS induces kidney mitochondrial abnormalities and dysfunction, which would be notable in the vulnerable renal medulla. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (ELAM, 0.1mg/kg SC q.d), and Lean controls (n=7 each). Single-kidney renal blood flow (RBF), glomerular-filtration-rate (GFR), and oxygenation were measured in-vivo, while cortical and medullary mitochondrial structure and function and renal injurious pathways were studied ex-vivo. Blood pressure was slightly elevated in MetS pigs, and their RBF and GFR were elevated. Blood oxygen level dependent magnetic resonance imaging demonstrated that this was associated with medullary hypoxia, whereas cortical oxygenation remained intact. MetS decreased renal content of the inner mitochondrial membrane cardiolipin, particularly the tetra-linoleoyl (C18:2) cardiolipin species, and altered mitochondrial morphology and function, particularly in the medullary thick ascending limb (mTAL). MetS also increased renal cytochrome-c-induced apoptosis, oxidative stress, and tubular injury. Chronic mitoprotection restored mitochondrial structure, ATP synthesis and antioxidant defenses, and decreased mitochondrial oxidative stress, medullary hypoxia, and renal injury. These findings implicate medullary mitochondrial damage in renal injury in experimental MetS, and position the mitochondria as a therapeutic target.