Dysregulated oxygen metabolism of the kidney by uremic toxins: review.
Because kidneys consume a large amount of oxygen and are relatively inefficient in oxygen uptake, they are susceptible to hypoxia, especially in patients with advanced chronic kidney disease accompanied by loss of peritubular capillaries. Accumulating evidence suggests that chronic tubulointerstitial hypoxia acts as a final common pathway leading to end-stage renal disease. Some biologically active uremic retention molecules, considered as uremic toxins, accumulate as the renal function declines, and at this moment, more than 90 bioactive uremic toxins have been identified. Uremic toxins per se have been proven to accelerate the progression of renal failure. However, the causal relationship between uremic toxin and tubulointerstitial hypoxia remains unclear. Our studies provided direct evidence that uremic toxin dysregulates oxygen metabolism in the kidney. Indoxyl sulfate (IS), a representative protein-bound uremic toxin, increased oxygen consumption in proximal renal tubules, decreased renal oxygenation, and consequently aggravated hypoxia in the remnant rat kidneys. The increase in tubular oxygen consumption by IS was dependent on sodium-potassium adenosine triphosphatase and oxidative stress. Our work also indicated a possible connection between IS and the desensitization of the oxygen-sensing mechanism in erythropoietin-producing cells, which may partly explain inadequate erythropoietin production in hypoxic kidneys of end-stage renal disease patients. Studies of uremic toxins will open a new avenue in development of novel therapeutic approaches of kidney disease.
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan.
Chih-Kang
CK
Chiang
Tetsuhiro
T
Tanaka
Masaomi
M
Nangaku
D000818:Animals; D049109:Cell Proliferation; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006706:Homeostasis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007200:Indican / Q000633:toxicity; D007668:Kidney / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism; D007684:Kidney Tubules / Q000098:blood supply / Q000166:cytology; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D014511:Uremia / Q000378:metabolism* / Q000473:pathology
D004921:Erythropoietin; D007200:Indican