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Title: Inhibition of renal Na{sup +}/H{sup +} exchange in cadmium-intoxicated rats

Abstract

Chronic exposure to cadmium (Cd) results in bicarbonaturia, leading to metabolic acidosis. To elucidate the mechanism(s) by which renal bicarbonate reabsorption is inhibited, we investigated changes in renal transporters and enzymes associated with bicarbonate reabsorption in Cd-intoxicated rats. Cd intoxication was induced by subcutaneous injections of CdCl{sub 2} (2 mg Cd/kg per day) for 3 weeks. Cd intoxication resulted in a significant reduction in V{sub max} of Na{sup +}/H{sup +} antiport with no changes in K{sub Na} in the renal cortical brush-border membrane vesicles (BBMV). Western blotting of BBM proteins and indirect immunohistochemistry in renal tissue sections, using an antibody against Na{sup +}/H{sup +} exchange-3 (NHE3), showed a diminished expression of NHE3 protein in the BBM. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that NHE3 mRNA expression was reduced in the renal cortex. The activity of carbonic anhydrase IV (CA IV) in BBM was not changed. The protein abundance of Na{sup +}-HCO{sub 3}{sup -} cotransporter-1 (NBC1) in whole kidney membrane fractions was slightly attenuated, whereas that of the Na{sup +}-K{sup +}-ATPase {alpha}-subunit was markedly elevated in Cd-intoxicated animals. These results indicate that Cd intoxication impairs NHE3 expression in the proximal tubule, thereby reducing the capacity for bicarbonate reabsorption, leading tomore » bicarbonaturia in an intact animal.« less

Authors:
 [1];  [1];  [1];  [1];  [2]
  1. Department of Physiology, Kosin University College of Medicine, Busan 602-702 (Korea, Republic of)
  2. Department of Physiology, Kosin University College of Medicine, Busan 602-702 (Korea, Republic of). E-mail: yspark@ns.kosinmed.or.kr
Publication Date:
OSTI Identifier:
20721780
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 204; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2004.08.021; PII: S0041-008X(04)00410-7; Copyright (c) 2004 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACID CARBONATES; ANTIBODIES; CADMIUM CHLORIDES; CARBONIC ANHYDRASE; CHRONIC EXPOSURE; INHIBITION; POLYMERASE CHAIN REACTION; POTASSIUM IONS; RATS; SODIUM IONS; SUBCUTANEOUS INJECTION; TRANSCRIPTION; TUBULES

Citation Formats

Ahn, Do Whan, Chung, Jin Mo, Kim, Jee Yeun, Kim, Kyoung Ryong, and Park, Yang Saeng. Inhibition of renal Na{sup +}/H{sup +} exchange in cadmium-intoxicated rats. United States: N. p., 2005. Web. doi:10.1016/j.taap.2004.08.021.
Ahn, Do Whan, Chung, Jin Mo, Kim, Jee Yeun, Kim, Kyoung Ryong, & Park, Yang Saeng. Inhibition of renal Na{sup +}/H{sup +} exchange in cadmium-intoxicated rats. United States. doi:10.1016/j.taap.2004.08.021.
Ahn, Do Whan, Chung, Jin Mo, Kim, Jee Yeun, Kim, Kyoung Ryong, and Park, Yang Saeng. Fri . "Inhibition of renal Na{sup +}/H{sup +} exchange in cadmium-intoxicated rats". United States. doi:10.1016/j.taap.2004.08.021.
@article{osti_20721780,
title = {Inhibition of renal Na{sup +}/H{sup +} exchange in cadmium-intoxicated rats},
author = {Ahn, Do Whan and Chung, Jin Mo and Kim, Jee Yeun and Kim, Kyoung Ryong and Park, Yang Saeng},
abstractNote = {Chronic exposure to cadmium (Cd) results in bicarbonaturia, leading to metabolic acidosis. To elucidate the mechanism(s) by which renal bicarbonate reabsorption is inhibited, we investigated changes in renal transporters and enzymes associated with bicarbonate reabsorption in Cd-intoxicated rats. Cd intoxication was induced by subcutaneous injections of CdCl{sub 2} (2 mg Cd/kg per day) for 3 weeks. Cd intoxication resulted in a significant reduction in V{sub max} of Na{sup +}/H{sup +} antiport with no changes in K{sub Na} in the renal cortical brush-border membrane vesicles (BBMV). Western blotting of BBM proteins and indirect immunohistochemistry in renal tissue sections, using an antibody against Na{sup +}/H{sup +} exchange-3 (NHE3), showed a diminished expression of NHE3 protein in the BBM. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that NHE3 mRNA expression was reduced in the renal cortex. The activity of carbonic anhydrase IV (CA IV) in BBM was not changed. The protein abundance of Na{sup +}-HCO{sub 3}{sup -} cotransporter-1 (NBC1) in whole kidney membrane fractions was slightly attenuated, whereas that of the Na{sup +}-K{sup +}-ATPase {alpha}-subunit was markedly elevated in Cd-intoxicated animals. These results indicate that Cd intoxication impairs NHE3 expression in the proximal tubule, thereby reducing the capacity for bicarbonate reabsorption, leading to bicarbonaturia in an intact animal.},
doi = {10.1016/j.taap.2004.08.021},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 204,
place = {United States},
year = {Fri Apr 01 00:00:00 EST 2005},
month = {Fri Apr 01 00:00:00 EST 2005}
}
  • Amiloride-sensitive Na/sup +/-H/sup +/ exchange activity in brush-border membrane vesicles isolated from male rat proximal tubules was decreased in the senescent rat (24 mo) compared with the young adult (6 mo). There was no significant loss in Na/sup +/-H/sup +/ exchange activity in the kidneys of animals between 6 and 18 mo of age. Amiloride-insensitive /sup 22/Na/sup +/ uptake and the rate of pH gradient dissipation were not altered during aging. The decrease in sodium-dependent (/sup 32/P) phosphate transport preceded the decline in Na/sup +/-H/sup +/ exchange activity by at least 6 mo. Sodium-dependent D-(/sup 3/H) glucose transport was notmore » significantly altered during aging. Thus various renal plasma membrane transport functions were affected differently in the aging rat. The decrease in Na/sup +/-H/sup +/ exchange activity during aging contrasted with the increase in exchange activity reported previously in acute ablation models of chronic renal failure.« less
  • To obtain further information on the negative calcium balance cased by Cd, the factors associated with serum calcium and phosphorus homeostasis other than inhibition of intestinal calcium absorption were studied by using cyclic 3{prime},4{prime}-adenosine monophosphate (cAMP). In rats exposed to Cd for 30 d, the levels of urinary excretion of cAMP after treatment with parathyroid hormone (PTH), parathyroidectomy (PTX), or 1{alpha}-hydroxycholecalciferol (1{alpha}-OH-D{sub 3}) showed almost the same patterns as those of control rats: the response of urinary cAMP to treatment with PTH was not influenced by continuous oral administration of Cd. On the other hand, in rats exposed to Cdmore » for 90 d without the other three treatments, the amount of urinary excretion of cAMP was markedly higher than in control rats. In PTX rats exposed to 90 d of Cd, urinary cAMP was uncharged, but it was markedly increased when the parathyroid was intact, with or without treatment with PTX. This phenomenon indicated hyperparathyroidemia in response to continuous oral administration of continuous oral administration of Cd for 90 d. The negative calcium balance with hyperparathyroidemia occurred after continuous oral administration of Cd and developed via increased urinary excretion of calcium. Urinary excretion of cAMP in Cd-exposed rats was unaffected by the administration of 1{alpha}-OH-D{sub 3}.« less
  • Most HCO3- reabsorption in proximal tubules occurs via electroneutral Na+/H+ exchange in brush border membranes (BBMS) and electrogenic Na+:CO3=:HCO3- cotransport in basolateral membranes (BLMS). Since potassium depletion (KD) increases HCO3- reabsorption in proximal tubules, we evaluated these transport systems using BBM and BLM vesicles, respectively, from control (C) and KD rats. Feeding rats a potassium deficient diet for 3-4 wk resulted in lower plasma (K+) (2.94 mEq/liter, KD vs. 4.47 C), and higher arterial pH (7.51 KD vs. 7.39 C). KD rats gained less weight than C but had higher renal cortical weight. Influx of 1 mM 22Na+ at 5more » s (pHo 7.5, pHi 6.0, 10% CO2, 90% N2) into BLM vesicles was 44% higher in the KD group compared to C with no difference in equilibrium uptake. The increment in Na+ influx in the KD group was DIDS sensitive, suggesting that Na+:CO3=:HCO3- cotransport accounted for the observed differences. Kinetic analysis of Na+ influx showed a Km of 8.2 mM in KD vs. 7.6 mM in C and Vmax of 278 nmol/min/mg protein in KD vs. 177 nmol/min/mg protein in C. Influx of 1 mM 22Na+ at 5 s (pHo 7.5, pHi 6.0) into BBM vesicles was 34% higher in the KD group compared to C with no difference in equilibrium uptake. The increment in Na+ influx in the KD group was amiloride sensitive, suggesting that Na+/H+ exchange was responsible for the observed differences. Kinetic analysis of Na+ influx showed a Km of 6.2 mM in KD vs. 7.1 mM in C and Vmax of 209 nmol/min/mg protein in KD vs. 144 nmol/min/mg protein in C. Uptakes of Na(+)-dependent (3H)glucose into BBM and (14C)succinate into BLM vesicles were not different in KD and C groups, suggesting that the Na+/H+ exchanger and Na+:CO3=:HCO3- cotransporter activities were specifically altered in KD.« less
  • Na -H exchange activity, i.e., amiloride-sensitive Na and H flux, in renal proximal tubule brush border (luminal) membrane vesicles was increased in the hyperthyroid rat and decreased in the hypothyroid rat, relative to the euthyroid animal. A positive correlation was found between Na -H exchange activity and serum concentrations of thyroxine (T4) and triiodothyronine (T3). The thyroid status of the animal did not alter amiloride-insensitive Na uptake. The rate of passive pH gradient dissipation was higher in membrane vesicles from hyperthyroid rats compared to the rate in vesicles from hypothyroid animals, a result which would tend to limit the increasemore » in Na uptake in vesicles from hyperthyroid animals. Na -dependent phosphate uptake was increased in membrane vesicles from hyperthyroid rats; Na -dependent D-glucose and L-proline uptakes were not changed by the thyroid status of the animal. The effect of thyroid hormones in increasing the uptake of Na in the brush border membrane vesicle is consistent with the action of the hormones in enhancing renal Na reabsorption.« less