Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress.
In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22(phox) showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.
Palm
Fredrik
F
Department of Medical Cell Biology, Uppsala University, Sweden.
Nangaku
Masaomi
M
Fasching
Angelica
A
Tanaka
Tetsuhiro
T
Nordquist
Lina
L
Hansell
Peter
P
Kawakami
Takahisa
T
Nishijima
Fuyuhiko
F
Fujita
Toshiro
T
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002244:Carbon / Q000494:pharmacology; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007200:Indican / Q000097:blood / Q000378:metabolism*; D007211:Indoles; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009392:Nephrectomy; D010042:Ouabain / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014511:Uremia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology
D000098:Acetophenones; D004791:Enzyme Inhibitors; D007211:Indoles; D010087:Oxides; D010042:Ouabain; D002244:Carbon; C030374:indole; C040896:AST 120; C056165:acetovanillone; D019255:NADPH Oxidases; C086986:CYBA protein, human; C515768:Cyba protein, rat; D000254:Sodium-Potassium-Exchanging ATPase; D007200:Indican