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Maleic acid-induced proximal tubulopathy: Na:K pump inhibition
1Department of Medicine, Northwestern University, Chicago, IL.
Abstract:
Maleic acid (MA) administration to experimental animals induces a rapid, reversible, complex dysfunction of the renal tubule resembling Fanconi's syndrome. The intent of this work was to characterize the changes in the Na:K pump along the nephron during the development and recovery from MA injury to better define the site of damage and to correlate the observed changes in Na:K pump function with alterations in metabolic function. Male Sprague Dawley rats were studied before and 2 and 24 h after the injection of MA (100 mg/kg iv). MA induced an early and reversible decline in Na:K pump activity in the proximal convoluted tubule (PCT) from 2,324 +/- 61 to 1,446 +/- 55 pmol/mm.h (P < 0.001). This decrement was transient because enzyme activity returned to near baseline by 24 h after MA administration. The changes in Na:K pump activity were restricted to the PCT because no change in pars rectae, in medullary thick ascending limb, or in medullary collecting tubules was observed. PCT obtained from MA-treated rats 2 h after drug injection showed a decline in 14CO2 formation from radiolabeled glutamine, implying impaired oxidation of the carbon skeleton of the amino acid. This decline was transient with recovery of oxidative rates to normal 24 h after MA administration. It was concluded that a reversible, segment-specific impairment in PCT Na:K pump occurs early after the administration of MA. The decline in PCT Na:K pump activity is paralleled by a decrement in oxidative metabolism and may underlie the many consequences of this model of proximal tubulopathy that are reflections of impairment in sodium-dependent transport processes.
Insights
Maleic acid (MA) causes temporary kidney damage, specifically affecting the sodium-potassium (Na:K) pump in the proximal convoluted tubule (PCT). This impairment in the Na:K pump and metabolic function recovers within 24 hours.
Area of Science:
- Nephrology
- Renal Physiology
- Biochemistry
Background:
- Maleic acid (MA) is a known nephrotoxin that induces a reversible renal tubule dysfunction resembling Fanconi's syndrome in experimental models.
- Understanding the specific cellular mechanisms and the site of MA-induced kidney injury is crucial for defining therapeutic targets.
Purpose of the Study:
- To investigate the alterations in the sodium-potassium (Na:K) pump activity along the nephron during the development and recovery from maleic acid injury.
- To correlate changes in Na:K pump function with metabolic alterations in the kidney.
Main Methods:
- Male Sprague Dawley rats were administered maleic acid (100 mg/kg iv).
- Na:K pump activity was measured in different segments of the nephron at baseline, 2 hours, and 24 hours post-administration.
- Oxidative metabolism (14CO2 formation from glutamine) was assessed in proximal convoluted tubule segments.
Main Results:
- Maleic acid induced a rapid and reversible decline in Na:K pump activity specifically in the proximal convoluted tubule (PCT).
- No significant changes in Na:K pump activity were observed in other nephron segments (pars rectae, thick ascending limb, collecting tubules).
- A transient decrease in glutamine oxidation was observed in PCTs 2 hours after MA administration, indicating impaired metabolic function.
Conclusions:
- Maleic acid causes a reversible, segment-specific impairment of the Na:K pump in the PCT.
- This impairment in Na:K pump activity is paralleled by a reduction in oxidative metabolism.
- These findings suggest that MA-induced proximal tubulopathy involves early, reversible damage to PCT Na:K pump function and metabolism.
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