Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.
The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.
Department of Biomedical Engineering, School of Engineering, Mercer University, Macon, Georgia.
Joanna L
JL
Thomas
Division of Nephrology and Hypertension, Department of Medicine, University of California, San Diego, and VA San Diego Healthcare System, San Diego, California.
Hai
H
Pham
Division of Nephrology and Hypertension, Department of Medicine, University of California, San Diego, and VA San Diego Healthcare System, San Diego, California.
Ying
Y
Li
Division of Nephrology and Hypertension, Department of Medicine, University of California, San Diego, and VA San Diego Healthcare System, San Diego, California.
Elanore
E
Hall
National Center for Microscopy and Imaging Research, La Jolla, California.
Guy A
GA
Perkins
Center for Aging and Associated Diseases, Helmy Institute of Medical Science, Zewail City of Science and Technology, Giza, Egypt; and.|Department of Anesthesiology, University of California, San Diego, California and VA San Diego Healthcare System, San Diego, California.
Sameh S
SS
Ali
Department of Anesthesiology, University of California, San Diego, California and VA San Diego Healthcare System, San Diego, California.
Hemal H
HH
Patel
Division of Nephrology and Hypertension, Department of Medicine, University of California, San Diego, and VA San Diego Healthcare System, San Diego, California; p1singh@ucsd.edu.
Prabhleen
P
Singh
D000255:Adenosine Triphosphate / Q000378:metabolism; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010100:Oxygen / Q000097:blood*; D010101:Oxygen Consumption / Q000187:drug effects*; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D065608:Renal Reabsorption / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D000600:Amino Acids, Dicarboxylic; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013481:Superoxides; D000255:Adenosine Triphosphate; D012964:Sodium; D010100:Oxygen; C040947:oxalylglycine
CKD; hypoxia; metabolism; mitochondria; oxygenation