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Published on: November 7, 2017
Dysregulated oxygen metabolism of the kidney by uremic toxins: review
Chih-Kang Chiang1, Tetsuhiro Tanaka, Masaomi Nangaku
1Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan.
Abstract:
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.
Insights
Uremic toxins, like indoxyl sulfate, worsen kidney hypoxia by increasing oxygen use in tubules. This discovery offers new therapeutic targets for chronic kidney disease patients.
Area of Science:
- Nephrology
- Physiology
- Toxicology
Background:
- Kidneys are oxygen-sensitive and prone to hypoxia, a key factor in chronic kidney disease (CKD) progression.
- Tubulointerstitial hypoxia is a common pathway to end-stage renal disease.
- Uremic toxins accumulate in CKD, accelerating renal failure, but their link to hypoxia is unclear.
Purpose of the Study:
- To investigate the causal relationship between uremic toxins and tubulointerstitial hypoxia.
- To determine if uremic toxins directly impact kidney oxygen metabolism.
Main Methods:
- Utilized remnant rat kidney models.
- Measured oxygen consumption and oxygenation in renal tubules.
- Investigated the role of sodium-potassium adenosine triphosphatase and oxidative stress.
- Examined the effect of indoxyl sulfate (IS) on erythropoietin-producing cells.
Main Results:
- Indoxyl sulfate (IS), a protein-bound uremic toxin, significantly increased oxygen consumption in proximal renal tubules.
- IS administration led to decreased renal oxygenation and aggravated hypoxia in remnant kidneys.
- Increased tubular oxygen consumption by IS was dependent on sodium-potassium adenosine triphosphatase and oxidative stress.
- IS may desensitize oxygen-sensing mechanisms in erythropoietin-producing cells, potentially explaining reduced erythropoietin levels.
Conclusions:
- Uremic toxins, exemplified by IS, directly dysregulate kidney oxygen metabolism, contributing to hypoxia.
- This provides a mechanistic link between uremic toxins and the progression of kidney disease.
- Targeting uremic toxins offers a potential therapeutic strategy for mitigating hypoxia and treating kidney disease.
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