Dynamic interactions between integrative physiology and molecular medicine: The key to understand the mechanism of action of aldo sterone in the kidney

2000 ◽  
Vol 78 (8) ◽  
pp. 587-594 ◽  
Author(s):  
Mitchell L Halperin ◽  
Kamel S Kamel
Keyword(s):  
Kidney Stones ◽  
Collecting Duct ◽  
Molecular Medicine ◽  
Cortical Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Dynamic Interactions ◽  
Integrative Physiology ◽  
Base Balance ◽  
Big Picture

Our objective is to illustrate how an approach that integrates new insights from molecular biology and traditional physiology can lead to the development of new concepts. This dynamic interaction is illustrated by examining the steps taken to improve our understanding of the renal actions of aldosterone. We began by defining the big picture of what aldosterone does in the kidney. This led to the conclusion that aldosterone must at times become a sodium chloride-retaining hormone, while at other times it must function primarily or exclusively as a kaliuretic hormone. The second step was to define the major molecular actions of this hormone. Acting on the principal cells in the cortical collecting duct (CCD), aldosterone leads to the insertion of active epithelial sodium ion channels (ENaC) in their luminal membranes. This active ENaC, however, does not distinguish between the two major renal actions of aldosterone. Accordingly, we returned to integrative physiology and examined a possible role of renal and non-renal events. We implicated the potential importance of the delivery of bicarbonate ions to the CCD to determine which effect of aldosterone will become manifest. This, however, required that we reconsider some of the traditional views in interpretation of acid-base balance. At the clinical level, this global view can help us understand why, for example, a low dietary intake of potassium salts might predispose a person to an elevated blood pressure. Using a similar approach, it is possible to understand how the risk of the formation of kidney stones can be minimized.Key words: acid-base, hypertension, integrative physiology, kidney stones, potassium, sodium.

(PRO)RENIN RECEPTOR IN THE KIDNEY: FUNCTION AND SIGNIFICANCE

2021 ◽  
Author(s):  
Gertrude Arthur ◽  
Jeffrey L. Osborn ◽  
Frederique B. Yiannikouris
Keyword(s):  
Intracellular Signaling ◽  
Collecting Duct ◽  
Renin Angiotensin System ◽  
Cortical Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Kidney Fibrosis ◽  
Prorenin Receptor ◽  
Base Balance ◽  
And Function

Prorenin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin has been shown to be multifunctional. In addition to its role in the renin angiotensin system (RAS), PRR also transduces several intracellular signaling molecules and is a component of the vacuolar H+-ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney namely the macula densa, podocyte, proximal and distal convoluted tubule and the principal cells of the collecting duct and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.

Regulation of AE2 mRNA expression in the cortical collecting duct by acid/base balance

1998 ◽  
Vol 274 (3) ◽  
pp. F596-F601 ◽  
Author(s):  
Géza Fejes-Tóth ◽  
Erzsébet Rusvai ◽  
Emily S. Cleaveland ◽  
Anikó Náray-Fejes-Tóth
Keyword(s):  
Mrna Expression ◽  
Collecting Duct ◽  
Cell Types ◽  
Alkaline Media ◽  
Mrna Levels ◽  
Intercalated Cells ◽  
Cortical Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance

AE2 mRNA and protein is expressed in several nephron segments, one of which is the cortical collecting duct (CCD). However, the distribution of AE2 among the different cell types of the CCD and the function of AE2 in the kidney are not known. The purpose of this study was to determine the distribution of AE2 mRNA among the three CCD cell types and to examine the effects of changes in acid/base balance on its expression. Following NH4Cl (acid) or NaHCO3 (base) loading of rabbits for ∼18 h, CCD cells were isolated by immunodissection. AE2 mRNA levels were determined by RT-PCR and were normalized for β-actin levels. We found that CCD cells express high levels of AE2 mRNA (∼500 copies/cell). AE2 mRNA levels were significantly higher in CCD cells originating from base-loaded than acid-loaded rabbits, with an average increase of 3.7 ± 1.07-fold. The effect of pH on AE2 mRNA levels was also tested directly using primary cultures of CCD cells. CCD cells incubated in acidic media expressed significantly lower levels of AE2 mRNA than those in normal or alkaline media. Experiments with isolated principal cells, α-intercalated cells, and β-intercalated cells (separated by fluorescence-activated cell sorting) demonstrated that AE2 mRNA levels are comparable in the three collecting duct cell subtypes and are similarly regulated by changes in acid/base balance. Based on these results, we conclude that adaptation to changes in extracellular H+ concentration is accompanied by opposite changes in AE2 mRNA expression. The observations that AE2 mRNA is not expressed in a cell-type-specific manner and that changes in acid/base balance have similar effects on each CCD cell subtype suggest that AE2 might serve a housekeeping function rather than being the apical anion exchanger of β-intercalated cells.

Expression of colonic H-K-ATPase mRNA in cortical collecting duct: regulation by acid/base balance

1995 ◽  
Vol 269 (4) ◽  
pp. F551-F557 ◽  
Author(s):  
G. Fejes-Toth ◽  
E. Rusvai ◽  
K. A. Longo ◽  
A. Naray-Fejes-Toth
Keyword(s):  
Amino Acid ◽  
Collecting Duct ◽  
Predicted Amino Acid Sequence ◽  
Cortical Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Pcr Product ◽  
Exact Function ◽  
Degenerate Oligonucleotide ◽  
Base Balance

In addition to the gastric isoform of H-K-ATPase, the colonic isoform is also expressed in the kidney, but its intrarenal localization and exact function are not known. The goal of this study was to determine whether the colonic H-K-ATPase is expressed in the rabbit cortical collecting duct (CCD) and whether it is regulated by changes in acid/base balance. With quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) with RNA isolated from immunodissected rabbit CCD cells and degenerate oligonucleotide primers, a PCR product of the predicted size (approximately 430 bp) was amplified. The amplified DNA was further characterized by nested PCR and sequencing. Direct sequencing of the 434-bp PCR product revealed 83% identity at the nucleotide level and an 80.4% identity at the deduced amino acid level to the rat colonic H-K-ATPase. With the same primers and cDNA originating from rabbit distal colon, a DNA fragment with a size and nucleotide sequence identical to that originating from CCD cells was amplified. Furthermore, using PCR screening, we isolated and sequenced a 1.5-kb cDNA clone from a rabbit CCD library. The predicted amino acid sequence of the protein encoded by this cDNA is 85 and 82% identical to the corresponding regions of the guinea pig and rat colonic H-K-ATPase, respectively, and 70% identical to the H-K-ATPase recently cloned from Bufo marinus, whereas it shows only 45 and 42% homology to the rat Na-K-ATPase alpha 1-subunit and the rat gastric H-K-ATPase, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulated expression of pendrin in rat kidney in response to chronic NH4Cl or NaHCO3 loading

2003 ◽  
Vol 284 (3) ◽  
pp. F584-F593 ◽  
Author(s):  
Sebastian Frische ◽  
Tae-Hwan Kwon ◽  
Jørgen Frøkiær ◽  
Kirsten M. Madsen ◽  
Søren Nielsen
Keyword(s):  
Plasma Membrane ◽  
Sodium Intake ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Apical Plasma Membrane ◽  
Cortical Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Control Value ◽  
Base Balance

The anion exchanger pendrin is present in the apical plasma membrane of type B and non-A-non-B intercalated cells of the cortical collecting duct (CCD) and connecting tubule and is involved in HCO[Formula: see text]secretion. In this study, we investigated whether the abundance and subcellular localization of pendrin are regulated in response to experimental metabolic acidosis and alkalosis with maintained water and sodium intake. NH4Cl loading (0.033 mmol NH4Cl/g body wt for 7 days) dramatically reduced pendrin abundance to 22 ± 4% of control values ( n = 6, P < 0.005). Immunoperoxidase labeling for pendrin showed reduced intensity in NH4Cl-loaded animals compared with control animals. Moreover, double-label laser confocal microscopy revealed a reduction in the fraction of cells in the CCD exhibiting pendrin labeling to 65% of the control value ( n = 6, P < 0.005). Conversely, NaHCO3 loading (0.033 mmol NaHCO3/g body wt for 7 days) induced a significant increase in pendrin expression to 153 ± 11% of control values ( n = 6, P < 0.01) with no change in the fraction of cells expressing pendrin. Immunoelectron microscopy revealed no major changes in the subcellular distribution, with abundant labeling in both the apical plasma membrane and the intracellular vesicles in all conditions. These results indicate that changes in pendrin protein expression play a key role in the well-established regulation of HCO[Formula: see text] secretion in the CCD in response to chronic changes in acid-base balance and suggest that regulation of pendrin expression may be clinically important in the correction of acid-base disturbances.

Decrease in N-ethylmaleimide-sensitive ATPase activity in collecting duct by metabolic alkalosis

1990 ◽  
Vol 68 (8) ◽  
pp. 1119-1123 ◽  
Author(s):  
Lal C. Garg ◽  
Neelam Narang
Keyword(s):  
Atpase Activity ◽  
Metabolic Alkalosis ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Control Group ◽  
Cortical Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Significant Difference ◽  
Base Balance

Changes in systemic acid – base balance are known to influence acidification in the collecting duct. The H+ secretion in the collecting duct has been shown to be an electrogenic process and it has been suggested that an H-ATPase sensitive to inhibition by N-ethylmaleimide (NEM) is responsible for H+ secretion. This study was designed to determine the effect of metabolic alkalosis on NEM-sensitive ATPase activity in the microdissected segments of the distal nephron. Metabolic alkalosis was produced by giving NaHCO3 to normal rats for 7 days. The plasma total CO2 concentration in the experimental group was 31.5 ± 1.8 mM compared with 23.4 ± 1.0 mM in the control group. NEM-sensitive ATPase activity was significantly lower in the cortical collecting duct and in the outer and inner medullary collecting ducts of alkali-loaded rats than those of control rats. There was no significant difference in the enzyme activity between the two groups of animals in the other nephron segments examined. Our results suggest that NEM-sensitive H-APTase activity in all three segments of the collecting duct is modulated by the acid – base status of the animal.Key words: collecting duct, H-ATPase, electrogenic H-pump, metabolic alkalosis, rat kidney.

Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake

2000 ◽  
Vol 279 (3) ◽  
pp. F459-F467 ◽  
Author(s):  
Gheun-Ho Kim ◽  
Stephen W. Martin ◽  
Patricia Fernández-Llama ◽  
Shyama Masilamani ◽  
Randall K. Packer ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Na Channel ◽  
Thick Ascending Limb ◽  
Acid Base Balance ◽  
Acid Base ◽  
Opposite Pattern ◽  
Α Subunit ◽  
Base Balance ◽  
Acid Loading

Increased systemic acid intake is associated with an increase in apical Na/H exchange in the renal proximal tubule mediated by the type 3 Na/H exchanger (NHE3). Because NHE3 mediates both proton secretion and Na absorption, increased NHE3 activity could inappropriately perturb Na balance unless there are compensatory changes in Na handling. In this study, we use semiquantitative immunoblotting of rat kidneys to investigate whether acid loading is associated with compensatory decreases in the abundance of renal tubule Na transporters other than NHE3. Long-term (i.e., 7-day) acid loading with NH4Cl produced large decreases in the abundances of the thiazide-sensitive Na-Cl cotransporter (TSC/NCC) of the distal convoluted tubule and both the β- and γ-subunits of the amiloride-sensitive epithelial Na channel (ENaC) of the collecting duct. In addition, the renal cortical abundance of the proximal type 2 Na-dependent phosphate transporter (NaPi-2) was markedly decreased. In contrast, abundances of the bumetanide-sensitive Na-K-2Cl cotransporter of the thick ascending limb and the α-subunit of ENaC were unchanged. A similar profile of changes was seen with short-term (16-h) acid loading. Long-term (7-day) base loading with NaHCO3resulted in the opposite pattern of response with marked increases in the abundances of the β- and γ-subunits of ENaC and NaPi-2. These adaptations may play critical roles in the maintenance in Na balance when changes in acid-base balance occur.

scholarly journals New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells

2012 ◽  
Vol 302 (10) ◽  
pp. C1421-C1433 ◽  
Author(s):  
Dennis Brown ◽  
Richard Bouley ◽  
Teodor G. Pǎunescu ◽  
Sylvie Breton ◽  
Hua A. J. Lu
Keyword(s):  
Cell Biology ◽  
Collecting Duct ◽  
Water Channel ◽  
Proton Pumping ◽  
Renal Tubules ◽  
Intercalated Cells ◽  
Acid Base Balance ◽  
Acid Base ◽  
Major Function ◽  
Base Balance

Maintaining tight control over body fluid and acid-base homeostasis is essential for human health and is a major function of the kidney. The collecting duct is a mosaic of two cell populations that are highly specialized to perform these two distinct processes. The antidiuretic hormone vasopressin (VP) and its receptor, the V2R, play a central role in regulating the urinary concentrating mechanism by stimulating accumulation of the aquaporin 2 (AQP2) water channel in the apical membrane of collecting duct principal cells. This increases epithelial water permeability and allows osmotic water reabsorption to occur. An understanding of the basic cell biology/physiology of AQP2 regulation and trafficking has informed the development of new potential treatments for diseases such as nephrogenic diabetes insipidus, in which the VP/V2R/AQP2 signaling axis is defective. Tubule acidification due to the activation of intercalated cells is also critical to organ function, and defects lead to several pathological conditions in humans. Therefore, it is important to understand how these “professional” proton-secreting cells respond to environmental and cellular cues. Using epididymal proton-secreting cells as a model system, we identified the soluble adenylate cyclase (sAC) as a sensor that detects luminal bicarbonate and activates the vacuolar proton-pumping ATPase (V-ATPase) via cAMP to regulate tubular pH. Renal intercalated cells also express sAC and respond to cAMP by increasing proton secretion, supporting the hypothesis that sAC could function as a luminal sensor in renal tubules to regulate acid-base balance. This review summarizes recent advances in our understanding of these fundamental processes.

Kidney collecting duct acid-base “regulon”

2006 ◽  
Vol 27 (3) ◽  
pp. 271-281 ◽  
Author(s):  
Lydie Cheval ◽  
Luciana Morla ◽  
Jean-Marc Elalouf ◽  
Alain Doucet
Keyword(s):  
Cell Proliferation ◽  
Metabolic Acidosis ◽  
Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Functional Studies ◽  
Expression Of Genes ◽  
Base Balance ◽  
Medullary Collecting Duct ◽  
Acid Base Disturbance

Kidneys are essential for acid-base homeostasis, especially when organisms cope with changes in acid or base dietary intake. Because collecting ducts constitute the final site for regulating urine acid-base balance, we undertook to identify the gene network involved in acid-base transport and regulation in the mouse outer medullary collecting duct (OMCD). For this purpose, we combined kidney functional studies and quantitative analysis of gene expression in OMCDs, by transcriptome and candidate gene approaches, during metabolic acidosis. Furthermore, to better delineate the set of genes concerned with acid-base disturbance, the OMCD transcriptome of acidotic mice was compared with that of both normal mice and mice undergoing an adaptative response through potassium depletion. Metabolic acidosis, achieved through an NH4Cl-supplemented diet for 3 days, not only induced acid secretion but also stimulated the aldosterone and vasopressin systems and triggered cell proliferation. Accordingly, metabolic acidosis increased the expression of genes involved in acid-base transport, sodium transport, water transport, and cell proliferation. In particular, >25 transcripts encoding proteins involved in urine acidification (subunits of H-ATPase, kidney anion exchanger, chloride channel Clcka, carbonic anhydrase-2, aldolase) were co-regulated during acidosis. These transcripts, which cooperate to achieve a similar function and are co-regulated during acidosis, constitute a functional unit that we propose to call a “regulon”.

HCO3- transport in rat CCD: rapid adaptation by in vivo but not in vitro alkalosis

1993 ◽  
Vol 264 (3) ◽  
pp. F435-F440
Author(s):  
J. D. Gifford ◽  
M. W. Ware ◽  
R. G. Luke ◽  
J. H. Galla
Keyword(s):  
Collecting Duct ◽  
Total Carbon ◽  
Cortical Collecting Duct ◽  
Rapid Adaptation ◽  
Acid Base Balance ◽  
Similar Time ◽  
Arterial Ph ◽  
Base Balance

Acute chloride-depletion alkalosis (CDA) in vivo results in sustained net total carbon dioxide (tCO2) secretion in vitro in the rat cortical collecting duct (CCD) for several hours. To determine whether altering in vitro pH and electrolytes similarly result in tCO2 secretion, CCD were incubated for 1 h at 37 degrees C in an alkalotic environment similar to in vivo arterial pH, PCO2, and electrolytes (pH 7.6, 40 mM HCO3). The in vitro alkalosis incubation had no effect on tCO2 transport. Second, alteration of the magnitude of vivo alkalosis was correlated with in vitro tCO2 transport. After generation of CDA by intraperitoneal dialysis against 154 mM HCO3-, rats received an infusion for 2.5 h of either 5% dextrose to maintain alkalosis or 154 mM NaCl at differing rates to partially correct or fully correct the systemic alkalosis. After in vitro isolation and perfusion, in vitro tCO2 flux correlated with in vivo Cl- balance (r2 = 0.82), serum HCO3- (r2 = 0.84), and arterial H+ concentration (r2 = 0.78), but not with K+ balance (r2 = 0.33). These findings suggest that: 1) the regulation of tCO2 transport in vitro correlates with the degree of systemic alkalosis and Cl- balance in vivo, and 2) simulating alkalotic pH and electrolytes in vitro does not rapidly alter transport as does in vivo CDA within a similar time. Taken together, pH and electrolyte changes alone cannot account for the rapid adaptation of tCO2 transport in the CCD, but an in vivo factor(s) contributes importantly to alter tCO2 transport in magnitude and direction that would tend to restore normal acid-base balance.

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