Substrate utilization by the distal nephron in dogs with chronic metabolic acidosis: studies with ethacrynic acid

1985 ◽  
Vol 63 (12) ◽  
pp. 1565-1569 ◽  
Author(s):  
Mitchell L. Halperin ◽  
Ching B. Chen
Keyword(s):  
Metabolic Acidosis ◽  
Ethacrynic Acid ◽  
Proximal Convoluted Tubule ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Distal Nephron ◽  
Chronic Metabolic Acidosis ◽  
Fractional Excretion Of Sodium ◽  
Renal Oxygen Consumption ◽  
Dog Kidney

Glutamine and lactate oxidations provide the bulk of ATP required for sodium reabsorption in the dog kidney during chronic metabolic acidosis. Indirect evidence has suggested that glutamine is oxidized in the proximal convoluted tubule; if this is true, lactate should be the major fuel of the more distal nephron sites. The purpose of these experiments was to determine which substrates were metabolized by the acidotic dog kidney when a significant proportion of sodium chloride reabsorption was inhibited in the thick ascending limb of the loop of Henle. Ethacrynic acid, a loop diuretic, caused the fractional excretion of sodium to increase from 1 to 34%. The glomerular filtration rate declined somewhat, but there was no significant change in the renal blood flow rate. Renal oxygen consumption declined in conjunction with the natriuresis. However, when the data were examined at a constant filtered load of sodium (a constant rate of ATP turnover), there was no reduction in glutamine uptake or glutamine conversion to ATP in the presence of this natriuretic agent. The major change observed concerned lactate metabolism, in the presence of ethacrynic acid, there was no longer a significant rate of lactate extraction. These data are best explained by assuming that glutamine is the fuel of the proximal convoluted tubule of the acidotic dog kidney, whereas lactate oxidation occurs principally in the nephron sites where sodium reabsorption was inhibited by ethacrynic acid.

NEM-sensitive ATPase activity in rat nephron: effect of metabolic acidosis and alkalosis

1990 ◽  
Vol 258 (2) ◽  
pp. F297-F304 ◽  
Author(s):  
S. Sabatini ◽  
M. E. Laski ◽  
N. A. Kurtzman
Keyword(s):  
Enzyme Activity ◽  
Metabolic Acidosis ◽  
Atpase Activity ◽  
Collecting Duct ◽  
Proximal Convoluted Tubule ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Chronic Metabolic Acidosis ◽  
Collecting Tubule ◽  
Cortical Collecting Tubule

The present study was designed to quantitate the amount and to map the localization of N-ethylmaleimide (NEM)-sensitive adenosinetriphosphatase (ATPase) activity in microdissected segments of the rat nephron. After complete nephron mapping the effect of chronic metabolic acidosis and alkalosis on enzyme activity was determined. In control animals the highest enzyme activity was found in the early proximal convoluted tubule of juxtamedullary nephrons; superficial early proximal tubule as well as medullary and cortical thick ascending limbs and collecting ducts also contained substantial activity. Enzyme activity in the papillary collecting duct before entry into the ducts of Bellini was 329 +/- 93 pmol.mm-1.h-1 (n = 8); after entry, however, enzyme activity was approximately one-fourth that value (60 +/- 9 pmol.mm-1.h-1, n = 8, P less than 0.01). No NEM-sensitive ATPase activity was found in the thin limbs of the loop of Henle. Enzyme activity increased in both the medullary and cortical thick ascending limbs as well as in the cortical collecting tubule in response to NH4Cl-induced chronic metabolic acidosis; in the cortical collecting duct, metabolic acidosis increased maximum activity (Vmax) but did not change Michaelis-Menten constant (Km). In the proximal convoluted tubule, enzyme activity decreased with metabolic acidosis. Bicarbonate loading had no effect on enzyme activity except in the most distal portion of the collecting duct where it was stimulated. These results show that NEM-sensitive ATPase activity exists throughout much of the rat nephron. These data suggest that both the cortical collecting tubule and thick ascending limb are regulatory sites of distal urinary acidification during acid loading.

scholarly journals Proximal and Distal Nephron-specific Adaptation to Furosemide

2021 ◽  
Author(s):  
Aram J. Krauson ◽  
Steven Schaffert ◽  
Elisabeth M. Walczak ◽  
Jonathan M. Nizar ◽  
Gwen M. Holdgate ◽  
...  
Keyword(s):  
Cell Number ◽  
Differentially Expressed ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Distal Nephron ◽  
Transcriptional Responses ◽  
Cell Hyperplasia ◽  
Diuretic Resistance ◽  
Nephron Segments ◽  
Renal Tubular

ABSTRACTFurosemide, a widely prescribed diuretic for edema-forming states, inhibits sodium reabsorption in the thick ascending limb of the nephron. Tubular adaptation to diuretics has been observed, but the range of mechanisms along the nephron has not been fully explored. Using morphometry, we show that furosemide induces renal tubular epithelial hyperplasia selectively in distal nephron segments. By comparison, we find progressive cellular hypertrophy in proximal and distal nephron segments. We next utilize single cell RNA sequencing of vehicle- and furosemide-treated mice to define potential mechanisms of diuretic resistance. Consistent with distal tubular cell hyperplasia, we detect a net increase in DCT cell number and Birc5, an anti-apoptotic and pro-growth gene, in a subset of DCT cells, as the most prominently up-regulated gene across the nephron. We also map a gradient of cell-specific transcriptional changes congruent with enhanced distal sodium transport. Furosemide stimulates expression of the mitogen IGF-1. Thus, we developed a mouse model of inducible deletion of renal tubular IGF-1 receptor and show reduced kidney growth and proximal, but not distal, tubular hypertrophy by furosemide. Moreover, genes that promote enhanced bioavailability of IGF-1 including Igfbp1 and Igfbp5 are significantly and differentially expressed in proximal tubular segments and correspond to IGF-1R-dependent hypertrophy. In contrast, downstream PI3-kinase signaling genes including Pdk1, Akt1, Foxo3, FKBP4, Eif2BP4, and Spp1 are significantly and differentially expressed in distal nephron segments and correspond to IGF-1R-independent hypertrophy. These findings highlight novel mechanisms of tubular remodeling and diuretic resistance, provide a repository of transcriptional responses to a common drug, and expand the implications of long-term loop diuretic use for human disease.

Adaptive changes in renal acidification in response to chronic respiratory acidosis

1985 ◽  
Vol 248 (4) ◽  
pp. F492-F499 ◽  
Author(s):  
R. L. Tannen ◽  
B. Hamid
Keyword(s):  
Metabolic Acidosis ◽  
Proton Transport ◽  
Respiratory Acidosis ◽  
Hydrogen Ion ◽  
Distal Nephron ◽  
Urine Ph ◽  
Chronic Metabolic Acidosis ◽  
Adaptive Changes ◽  
Secretory Capacity

To examine whether chronic respiratory acidosis results in adaptive changes in renal acidification, rats were housed for 3 days in an environmental chamber with an ambient CO2 content of 10% and their kidneys were perfused in vitro according to two protocols. To assess hydrogen ion secretory capacity of the distal nephron, perfusions were carried out with a low bicarbonate concentration, in the absence of ammoniagenic substrate, and with saturating quantities of the buffer creatinine. Under these conditions, the titration of creatinine at a pH less than 6.0 (TA pH 6.0) reflects the H+ secretory capacity of a discrete functional segment of the distal nephron. Kidneys from rats with chronic respiratory acidosis exhibited a significantly lower urine pH and higher rate of TA pH 6.0 than controls perfused in this fashion, indicative of an adaptive increase in the distal nephron capacity for proton transport. This adaptation was comparable with that reported previously for rats exposed to chronic metabolic acidosis. Furthermore, evidence of adaptation persisted in the presence of amiloride (10(-5) M), suggesting that it reflects, at least in part, a sodium-independent mechanism of proton transport. Hydrogen ion secretion by the proximal nephron was assessed by performing standard bicarbonate titration curves with kidneys from rats with chronic respiratory acidosis, chronic metabolic acidosis, and controls using a perfusate equilibrated with 95% O2/5% CO2.(ABSTRACT TRUNCATED AT 250 WORDS)

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

2002 ◽  
Vol 282 (2) ◽  
pp. F341-F351 ◽  
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].

Effects of certain inhibitors on renal excretion of salt and water

1963 ◽  
Vol 205 (1) ◽  
pp. 117-122 ◽  
Author(s):  
James C. Strickler ◽  
Richard H. Kessler
Keyword(s):  
Atp Synthesis ◽  
Cation Transport ◽  
Sodium Reabsorption ◽  
Antimycin A ◽  
Negative Results ◽  
Renal Oxygen Consumption ◽  
Dog Kidney ◽  
Anesthetized Dogs ◽  
Direct Proportionality

The direct proportionality between renal oxygen consumption and sodium reabsorption suggests a linkage between cation transport and the electron transport system (ETS). We have studied the effects of in vitro inhibitors of the ETS on sodium reabsorption in the dog kidney. Compounds known to block O2 consumption or reduce tissue levels of adenosine triphosphate (ATP) were infused in millimolar quantities into a renal artery of anesthetized dogs. We observed a unilateral diuresis following the administration of cyanide, antimycin-A and iodoacetamide; no diuresis was observed following administration of 2,4-dinitrophenol, azide, and phlorizin. These latter agents block the synthesis or facilitate the degradation of ATP. Negative results were also observed with phthiocol (a naphthoquinone), malonate, and Amytal, inhibitors of specific substrates of ETS. We interpret our results as follows. Inhibition of sodium reabsorption by cyanide and antimycin-A supports the hypothesis that renal cation transport is dependent in part upon oxidative metabolism. The failure of phlorizin and 2,4-dinitrophenol to affect sodium reabsorption suggests that cation transport may be independent of ATP synthesis or concentration in renal tissues.

Ammonium carriers in medullary thick ascending limb

2001 ◽  
Vol 280 (1) ◽  
pp. F1-F9 ◽  
Author(s):  
Amel Attmane-Elakeb ◽  
Hassane Amlal ◽  
Maurice Bichara
Keyword(s):  
Metabolic Acidosis ◽  
Renal Medulla ◽  
Thick Ascending Limb ◽  
Renal Handling ◽  
Chronic Metabolic Acidosis ◽  
Nacl Absorption ◽  
Medullary Thick Ascending Limb ◽  
Collecting Ducts ◽  
Fine Regulation ◽  
Coordinated Effects

Absorption of NH4 + by the medullary thick ascending limb (MTAL) is a key event in the renal handling of NH4 +, leading to accumulation of NH4 +/NH3 in the renal medulla, which favors NH4 + secretion in medullary collecting ducts and excretion in urine. The Na+-K+(NH4 +)-2Cl−cotransporter (BSC1/NKCC2) ensures ∼50–65% of MTAL active luminal NH4 + uptake under basal conditions. Apical barium- and verapamil-sensitive K+/NH4 +antiport and amiloride-sensitive NH4 + conductance account for the rest of active luminal NH4 + transport. The presence of a K+/NH4 + antiport besides BSC1 allows NH4 + and NaCl absorption by MTAL to be independently regulated by vasopressin. At the basolateral step, the roles of NH3 diffusion coupled to Na+/H+ exchange or Na+/NH4 + exchange, which favors NH4 + absorption, and of Na+/K+(NH4 +)-ATPase, NH4 +-Cl− cotransport, and NH4 + conductance, which oppose NH4 +absorption, have not been quantitatively defined. The increased ability of the MTAL to absorb NH4 + during chronic metabolic acidosis involves an increase in BSC1 expression, but fine regulation of MTAL NH4 + transport probably requires coordinated effects on various apical and basolateral MTAL carriers.

scholarly journals Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis

2021 ◽  
Author(s):  
Bryn D. Webb ◽  
Hilary Hotchkiss ◽  
Pankaj Prasun ◽  
Bruce D. Gelb ◽  
Lisa Satlin
Keyword(s):  
Metabolic Acidosis ◽  
Membrane Potential ◽  
Basolateral Membrane ◽  
Loss Of Function ◽  
Distal Nephron ◽  
Chronic Metabolic Acidosis ◽  
Whole Exome ◽  
Hyperchloremic Metabolic Acidosis ◽  
Inwardly Rectifying ◽  
Basolateral Membrane Potential

AbstractKCNJ16 encodes Kir5.1 and acts in combination with Kir4.1, encoded by KCNJ10, to form an inwardly rectifying K+ channel expressed at the basolateral membrane of epithelial cells in the distal nephron. This Kir4.1/Kir5.1 channel is critical for controlling basolateral membrane potential and K+ recycling, the latter coupled to Na-K-ATPase activity, which determines renal Na+ handling. Previous work has shown that Kcnj16−/− mice and SSKcnj16−/− rats demonstrate hypokalemic, hyperchloremic metabolic acidosis. Here, we present the first report of a patient identified to have biallelic loss-of-function variants in KCNJ16 by whole exome sequencing who presented with chronic metabolic acidosis with exacerbations triggered by minor infections.

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