High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes.
Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration.
Division of Endocrinology, Department of Internal Medicine, Saint Louis University School of Medicine, Edward A. Doisy Research Center, 1100 South Grand Blvd., DRC 354, St. Louis, MO 63104, USA. Electronic address: shahgn@slu.edu.
Gul N
GN
Shah
Yoichi
Y
Morofuji
William A
WA
Banks
Tulin O
TO
Price
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005016:Ethoxzolamide / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D005947:Glucose / Q000008:administration & dosage*; D006943:Hyperglycemia / Q000503:physiopathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D020286:Pericytes / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077236:Topiramate
D002257:Carbonic Anhydrase Inhibitors; D017382:Reactive Oxygen Species; D000077236:Topiramate; D005632:Fructose; D005947:Glucose; D005016:Ethoxzolamide
6-ethoxy-2-benzothiazolesulfonamide (ethoxyzolamide); CAIs; Cerebral pericytes; Diabetes; ECAR; ETZ; HCO(−)(3); HG; IFN-γ; Microvasculature; Mitochondrial carbonic anhydrases; NG; OCR; ROS; Reactive oxygen species; Respiration; TOP; bicarbonate; high glucose; interferon gamma; mitochondrial carbonic anhydrase inhibitors; normal glucose; rate of acid efflux; rate of oxygen consumption; reactive oxygen species; topiramate