Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney

Chronic metabolic acidosis increases the activity of the proximal tubule apical membrane Na/H antiporter, which is encoded predominantly by the NHE3 isoform. The present studies examined the effect of chronic metabolic acidosis on apical membrane NHE3 protein abundance in rats. Rats subjected to NH4Cl in their drinking water developed a metabolic acidosis, which decreased in magnitude over 14 days. During this time, renal cortical brush-border membrane NHE3 protein abundance, assessed by Western blot, increased progressively (28% at 3 days, 59% at 7 days, and 90% at 14 days). Immunohistochemistry revealed that the acidosis-induced increase in NHE3 abundance occurred in the apical membranes of the S1 and S2 segments of the proximal tubule and the thick ascending limb. NHE3 mRNA abundance was not significantly increased in these animals, whereas phosphoenolpyruvate carboxykinase and glyceraldehyde-3-phosphate dehydrogenase mRNA abundances were significantly increased. These studies demonstrate that the increase in Na/H antiporter activity seen in metabolic acidosis involves an increase in NHE3 protein abundance, which is distributed along the proximal tubule and the thick ascending limb. In addition, these studies suggest that a component of this adaptation is unrelated to changes in NHE3 mRNA abundance.

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Inhibition of 25-hydroxyvitamin D3-1-hydroxylase by chronic metabolic acidosis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1982.243.4.e265 ◽

1982 ◽

Vol 243 (4) ◽

pp. E265-E271

Author(s):

G. S. Reddy ◽

G. Jones ◽

S. W. Kooh ◽

D. Fraser

Keyword(s):

Vitamin D ◽

Metabolic Acidosis ◽

Rat Kidney ◽

Ion Concentration ◽

Hydroxylase Activity ◽

Renal Metabolism ◽

Dihydroxyvitamin D3 ◽

Hydrogen Ion Concentration ◽

Chronic Metabolic Acidosis ◽

Negative Linear Correlation

Chronic metabolic acidosis had been shown to influence the renal metabolism of 25-hydroxyvitamin D3. Using the isolated perfused rat kidney model, we evaluated the rates of synthesis of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in vitamin D-depleted [D(-)] and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in vitamin D-replete [D(+)] rats. Metabolic acidosis was induced in both groups of rats by feeding aqueous ammonium chloride for 9 days. Kidneys isolated from D(-) acidotic rats (mean pH, 7.11) exhibited a decreased rate of 1,25(OH)2D3 synthesis (0.79 +/- 0.17 pmol produce . h-1 . g kidney-1) when compared with that (1.27 +/- 0.09) of D(-) nonacidotic (mean pH, 7.33) rats. There was a significant negative linear correlation between the rate of synthesis of 1,25(OH)2D3 and the hydrogen ion concentration of the animal (r = 0.79, P less than 0.005). The rate of synthesis of 24,25(OH)2D3 by the kidneys from D(+) acidotic (mean pH, 7.06) and nonacidotic (mean pH, 7.39) rats did not differ (0.81 +/- 0.21 vs. 0.60 +/- 0.12 pmol product . h-1 . g kidney-1). It is concluded that chronic acidosis suppressed 1-hydroxylase activity, but does not suppress 24-hydroxylase activity.

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Chronic metabolic acidosis upregulates rat kidney Na-HCO 3 − cotransporters NBCn1 and NBC3 but not NBC1

AJP Renal Physiology ◽

10.1152/ajprenal.00104.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. F341-F351 ◽

Cited By ~ 77

Author(s):

Tae-Hwan Kwon ◽

Christiaan Fulton ◽

Weidong Wang ◽

Ira Kurtz ◽

Jørgen Frøkiær ◽

...

Keyword(s):

Metabolic Acidosis ◽

Rat Kidney ◽

Free Access ◽

Thick Ascending Limb ◽

Acid Base Balance ◽

Acid Base ◽

Chronic Metabolic Acidosis ◽

Daily Water Intake ◽

Base Balance ◽

Access To Water

Several members of the Na-HCO[Formula: see text] cotransporter (NBC) family have recently been identified functionally and partly characterized, including rkNBC1, NBCn1, and NBC3. Regulation of these NBCs may play a role in the maintenance of intracellular pH and in the regulation of renal acid-base balance. However, it is unknown whether the expressions of these NBCs are regulated in response to changes in acid-base status. We therefore tested whether chronic metabolic acidosis (CMA) affects the abundance of these NBCs in kidneys using two conventional protocols. In protocol 1, rats were treated with NH4Cl in their drinking water (12 ± 1 mmol · rat−1 · day−1) for 2 wk with free access to water ( n = 8). Semiquantitative immunoblotting demonstrated that whole kidney abundance of NBCn1 and NBC3 in rats with CMA was dramatically increased to 995 ± 87 and 224 ± 35%, respectively, of control levels ( P < 0.05), whereas whole kidney rkNBC1 was unchanged (88 ± 14%). In protocol 2, rats were given NH4Cl in their food (10 ± 1 mmol · rat−1 · day−1) for 7 days, with a fixed daily water intake ( n = 6). Consistent with protocol 1, whole kidney abundances of NBCn1 (262 ± 42%) and NBC3 (160 ± 31%) were significantly increased compared with controls ( n = 6), whereas whole kidney rkNBC1 was unchanged (84 ± 17%). In both protocols, immunocytochemistry confirmed upregulation of NBCn1 and NBC3 with no change in the segmental distribution along the nephron. Consistent with the increase in NBCn1, measurements of pH transients in medullary thick ascending limb (mTAL) cells in kidney slices revealed two- to threefold increases in DIDS- sensitive, Na+-dependent HCO[Formula: see text] uptake in rats with CMA. In conclusion, CMA is associated with a marked increase in the abundance of NBCn1 in the mTAL and NBC3 in intercalated cells, whereas the abundance of NBC1 in the proximal tubule was not altered. The increased abundance of NBCn1 may play a role in the reabsorption of NH[Formula: see text] in the mTAL and increased NBC3 in reabsorbing HCO[Formula: see text].

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Acute and chronic metabolic acidosis interferes with aquaporin-2 translocation in the rat kidney collecting ducts

Hypertension Research ◽

10.1038/hr.2009.19 ◽

2009 ◽

Vol 32 (5) ◽

pp. 358-363 ◽

Cited By ~ 13

Author(s):

Tomohiko Mouri ◽

Takeaki Inoue ◽

Hiroshi Nonoguchi ◽

Yushi Nakayama ◽

Hiroki Miyazaki ◽

...

Keyword(s):

Metabolic Acidosis ◽

Rat Kidney ◽

Chronic Metabolic Acidosis ◽

Aquaporin 2 ◽

Collecting Ducts

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Chronic metabolic acidosis enhances NHE-3 protein abundance and transport activity in the rat thick ascending limb by increasing NHE-3 mRNA.

Journal of Clinical Investigation ◽

10.1172/jci119128 ◽

1997 ◽

Vol 99 (1) ◽

pp. 24-30 ◽

Cited By ~ 74

Author(s):

K Laghmani ◽

P Borensztein ◽

P Ambühl ◽

M Froissart ◽

M Bichara ◽

...

Keyword(s):

Metabolic Acidosis ◽

Thick Ascending Limb ◽

Protein Abundance ◽

Transport Activity ◽

Chronic Metabolic Acidosis

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Ammoniagenesis in kidney cortex mitochondria of the rat: role of the mitochondrial dicarboxylate anion transporter

Canadian Journal of Biochemistry ◽

10.1139/o78-004 ◽

1978 ◽

Vol 56 (1) ◽

pp. 23-28 ◽

Cited By ~ 12

Author(s):

Surinder Cheema-Dhadli ◽

Mitchell L. Halperin

Keyword(s):

Metabolic Acidosis ◽

Renal Cortex ◽

Rat Kidney ◽

Maximum Velocity ◽

Liver Mitochondria ◽

Kidney Cortex ◽

Chronic Metabolic Acidosis ◽

Kidney Mitochondria ◽

Anion Transporter

Since glutamine enters rat kidney mitochondria without exchange for an anion, the exit of its carbon skeleton must involve the dicarboxylate anion transporter (malate – inorganic phosphate) for ammoniagenesis to proceed. Therefore, this important mitochondrial anion transporter was studied in isolated renal cortex mitochondria. The phosphate concentration required for half-maximal rates of malate exit from renal cortex mitochondria of normal rats was 1.0 mM. This value was not decreased in renal cortex mitochondria from rats with chronic metabolic acidosis. The maximum velocity of the dicarboxylate transporter was not increased in renal cortex mitochondria from these acidotic rats. These kinetic parameters were similar in liver mitochondria. There was no acute activation of the dicarboxylate carrier when the incubation medium pH was lowered. Thus, there is no demonstrable activation of the dicarboxylate anion transporter in kidney cortex mitochondria of the rat with chronic metabolic acidosis. The significance of these results with respect to the regulation of renal ammoniagenesis is discussed.

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Metabolic acidosis has dual effects on sodium handling by rat kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00338.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. F322-F331 ◽

Cited By ~ 23

Author(s):

Somia Faroqui ◽

Sulaiman Sheriff ◽

Hassane Amlal

Keyword(s):

Metabolic Acidosis ◽

Collecting Duct ◽

Rat Kidney ◽

Distal Tubule ◽

Protein Abundance ◽

Water Control ◽

Volume Depletion ◽

Serum Aldosterone ◽

Access To Water ◽

Sodium Handling

Chronic metabolic acidosis (CMA) is associated with decreased NaCl reabsorption in the proximal tubule (PT). However, the effect of CMA on Na+ transport in the distal tubule (DT) and collecting duct (CD) is poorly understood. Rats were placed in metabolic cages and had access to water (control), 0.28 M NH4Cl, or 0.28 M KCl solutions in a pair-feeding protocol for 5 days (5d). Metabolic acidosis developed within 24 h in NH4Cl-, but not in KCl-loaded rats. Interestingly, NH4Cl- but not KCl-loaded rats exhibited a significant natriuresis after 24 h of treatment. Urinary Na+ excretion increased from 1.94 to 2.97 meq/24 h ( P < 0.001) and returned to below baseline level (1.67 meq/l) after 5d of CMA. The protein abundance of the cortical Na-Cl cotransporter (NCC) remained unchanged at 24 h, but increased significantly ( P < 0.01) after 5d of CMA. The protein abundance of α-, β-, and γ-subunits of the epithelial Na+ channel (ENaC) in the cortex decreased sharply during the first 24 h and then returned to baseline levels after 5d of CMA. Interestingly, Sgk1 expression decreased after 24 h (−31%, P < 0.05) and then returned to baseline after 5d of CMA. Nedd4–2 expression was not altered during CMA. CMA enhanced serum aldosterone levels by 54% and increased the expression of aldosterone synthase in the adrenal gland by 134% after 5d of CMA. In conclusion, metabolic acidosis has dual effects on urinary Na+ excretion. The early natriuresis results from decreased Na+ reabsorption in the PT and Sgk1-related decreased ENaC activity in the DT and CD. Aldosterone-induced upregulation of NCC, Sgk1, and ENaC likely contributes to the antinatriuretic phase of metabolic acidosis. This adaptation prevents Na+ wasting and volume depletion during chronic acid insult.

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