Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury

Abstract

Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and FoF1-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and FoF1-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI.

Is the Secret of VDAC Isoforms in Their Gene Regulation? Characterization of Human VDAC Genes Expression Profile, Promoter Activity, and Transcriptional Regulators

“…Mitochondria lacking VDAC ( VDAC1 −/−) are characterized by increased size, irregular and compacted cristae, and altered oxygen consumption either in oxidative either in glycolytic muscle fibers [ 11 ]. Other alterations have been detected in specific tissue injuries or pathologies, such as Alzheimer’s disease [ 15 , 16 ]. Impaired oxidative phosphorylation was detected in muscle biopsies of child patients affected by encephalomyopathy.…”

Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence

“…In this study, sympathetic activation induces mitochondrial disorders, including the reduction of the mitochondrial membrane proteins (VADC1 and COX IV), the increase in abnormal mitochondrial morphology (swollen mitochondria and fractured mitochondrial crest), and the vanishment of the mitochondrial membrane potential ( Figure 7 ). Closed or lost VDAC1 destroyed the integrity of the mitochondrial outer membranes ( 51 ), inhibited mitochondrial respiration, and exacerbated mitochondrial division ( 52 ). Besides, the lack of electron transport chain proteins, such as the cytochrome c oxidase family (like COX IV) ( 53 ), led to electron leakage, which produced ROS-like superoxide free radicals to trigger cellular senescence ( 54 ).…”

γ-Tocotrienol Protects against Mitochondrial Dysfunction, Energy Deficits, Morphological Damage, and Decreases in Renal Functions after Renal Ischemia

“…Plasma levels of creatinine were used as a marker of renal function. Blood was drawn while mice were euthanized, spun down and plasma was used to determine creatinine concentration using the Creatinine Reagent Set from Biotron Diagnostics (Hemet, CA, USA) and the manufacturer’s protocol, as reported previously [ 56 , 57 , 58 ]. Plasma creatinine levels were determined in all mice used in the four experimental groups described on page 3.…”

“…; Ovation Pharmaceuticals, Deerfield, IL, USA) and all surgical procedures were performed under sterile conditions. Following a midline incision of the abdomen, kidneys were exposed and decapsulated, and both renal hila were clamped for 35 min with small vascular clamps to induce bilateral renal ischemia as described previously [55][56][57][58]. While renal arteries of both kidneys were clamped, mice were placed on a heating pad that maintained a temperature of 37 • C. During that time, approximately 0.5 mL sterile saline was applied intraperitoneally to prevent fluid loss and dehydration.…”

“…Immediately after mice were euthanized, both kidneys were harvested, submerged in an ice-cold isolation buffer (10 mM Hepes, 225 mM mannitol, 75 mM sucrose, 2 mM EGTA, and 0.1% BSA, fatty acid free, pH 7.4) and dissected on ice as described previously [56][57][58]. Cortical tissue separated from the kidneys was homogenized in ice-cold isolation buffer and the homogenate was spun down at 1000× g 5 min at 4 • C. The supernatant resulting from this centrifugation was spun down at 15,000× g 15 min at 4 • C to obtain a mitochondrial pellet.…”