Metabolic acidosis in rats increases intestinal NHE2 and NHE3 expression and function

2002 ◽  
Vol 283 (1) ◽  
pp. G51-G56 ◽  
Author(s):  
Alvaro Lucioni ◽  
Christopher Womack ◽  
Mark W. Musch ◽  
Flavio L. Rocha ◽  
Cres Bookstein ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Ammonium Chloride ◽  
Brush Border ◽  
Cellular Differentiation ◽  
Mrna Levels ◽  
Northern Blots ◽  
Intestinal Physiology ◽  
Enhanced Expression ◽  
And Function

Chronic metabolic acidosis increases intestinal Na absorption, although through undefined mechanisms. Whether this occurs through enhanced expression and/or function of the brush-border Na+/H+ exchangers (NHE)2 and NHE3 is unknown. Metabolic acidosis was induced in rats by feeding ammonium chloride through their drinking water. Intestinal NHE activities were measured using brush-border 22Na+ uptake. Western and Northern blots measured changes in protein and mRNA expression, respectively. Acidosis occurred within 2 days of ammonium chloride feedings but increased after 6 days. NHE2 and NHE3 activities, protein expression, and mRNA levels increased in acidotic rats compared with controls. In contrast, basolateral NHE1 expression was not affected. Brush-border alkaline phosphatase showed no effect of metabolic acidosis on cellular differentiation. This study demonstrated a direct effect of metabolic acidosis on NHE2 and NHE3 activity, expression, and gene transcription. Metabolic acidosis is one of the few circumstances shown to affect NHE2 function and expression, thus providing insights into the role of NHE2 on intestinal physiology.

Effect of acidosis on PTH-dependent renal adenylate cyclase in phosphorus deprivation: role of G proteins

1990 ◽  
Vol 258 (6) ◽  
pp. F1640-F1649
Author(s):  
E. Bellorin-Font ◽  
R. Starosta ◽  
C. L. Milanes ◽  
C. Lopez ◽  
N. Pernalete ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Adenylate Cyclase ◽  
Maximal Activity ◽  
Phosphate Deprivation ◽  
Adp Ribosylation ◽  
Phosphate Depletion ◽  
Cortical Membranes ◽  
And Function ◽  
Gs Alpha

These studies examine the regulation of adenylate cyclase in renal cortical membranes from phosphate-deprived and phosphate-deprived acidotic dogs. Enzyme stimulation by parathyroid hormone (PTH) was decreased in phosphate deprivation [Vmax 1,578 +/- 169 vs. 2,581 +/- 219 pmol adenosine 3',5'-cyclic monophosphate (cAMP).mg protein-1 x 30 min-1 in controls, P less than 0.01]. Metabolic acidosis further decreased PTH-stimulated activity. Membranes from phosphate-deprived dogs showed a decrease in Gs alpha-content by cholera toxin-dependent ADP-ribosylation (174 +/- 18 arbitrary units vs. 266.4 +/- 13.6 in controls, P less than 0.01). Metabolic acidosis further decreased Gs alpha-content, P less than 0.01. Gi content by pertussis-dependent ADP-ribosylation was also lower in phosphate-deprived and phosphate-deprived acidotic animals. Gs function was examined by its property to protect the catalytic unit from inactivation by N-ethylmaleimide when preincubated with GTP gamma S. In controls, protection of inactivation was 80% of the maximal activity, whereas in phosphate deprivation protection was less than 50%. In conclusion, metabolic acidosis enhances adenylate cyclase resistance to PTH in phosphate deprivation. These alterations are associated with a decrease in the content and function of Gs alpha, suggesting a role of Gs in the renal adaptation to phosphate depletion and acidosis.

scholarly journals The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 265 ◽  
Author(s):  
Sathish Murali ◽  
Takwa Aroankins ◽  
Hanne Moeller ◽  
Robert Fenton
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Mouse Kidney ◽  
Body Water ◽  
Mrna Levels ◽  
E3 Ligases ◽  
Water Homeostasis ◽  
And Function

Aquaporin 2 (AQP2) mediates the osmotic water permeability of the kidney collecting duct in response to arginine vasopressin (VP) and is essential for body water homeostasis. VP effects on AQP2 occur via long-term alterations in AQP2 abundance and short-term changes in AQP2 localization. Several of the effects of VP on AQP2 are dependent on AQP2 phosphorylation and ubiquitylation; post-translational modifications (PTM) that modulate AQP2 subcellular distribution and function. Although several protein kinases, phosphatases, and ubiquitin E3 ligases have been implicated in AQP2 PTM, how AQP2 is deubiquitylated or the role of deubiquitylases (DUBS) in AQP2 function is unknown. Here, we report a novel role of the ubiquitin-specific protease USP4 in modulating AQP2 function. USP4 co-localized with AQP2 in the mouse kidney, and in mpkCCD14 cells USP4 and AQP2 abundance are increased by VP. AQP2 and USP4 co-immunoprecipitated from mpkCCD14 cells and mouse kidney, and in vitro, USP4 can deubiquitylate AQP2. In mpkCCD14 cells, shRNA mediated knockdown of USP4 decreased AQP2 protein abundance, whereas no changes in AQP2 mRNA levels or VP-induced cAMP production were detected. VP-induced AQP2 membrane accumulation in knockdown cells was significantly reduced, which was associated with higher levels of ubiquitylated AQP2. AQP2 protein half-life was also significantly reduced in USP4 knockdown cells. Taken together, the data suggest that USP4 is a key regulator of AQP2 deubiquitylation and that loss of USP4 leads to increased AQP2 ubiquitylation, decreased AQP2 levels, and decreased cell surface AQP2 accumulation upon VP treatment. These studies have implications for understanding body water homeostasis.

scholarly journals Preterm birth makes the immature intestine sensitive to feeding-induced intestinal atrophy

2005 ◽  
Vol 289 (4) ◽  
pp. R1212-R1222 ◽  
Author(s):  
Charlotte Reinhard Bjornvad ◽  
Mette Schmidt ◽  
Yvette Miata Petersen ◽  
Søren Krogh Jensen ◽  
Hanne Offenberg ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Brush Border ◽  
Enzyme Activities ◽  
Formula Feeding ◽  
Oral Feeding ◽  
Microbial Colonization ◽  
Milk Formula ◽  
Mrna Levels ◽  
Brush Border Enzyme ◽  
And Function

Preterm birth and formula feeding predispose to small intestinal dysfunction, which may lead to necrotizing enterocolitis (NEC). In piglets, we tested whether the physiological and environmental transitions occurring at birth affect the response of the immature intestine to enteral feeding. Pig fetuses (106 days gestation, term = 115 days) were prepared with esophageal feeding tubes and fed either sow's colostrum ( n = 8) or infant formula ( n = 7) in utero. After 24 h of oral feeding, the pig fetuses were delivered by cesarean section and their gastrointestinal morphology and function were compared with those of preterm newborn (NB) littermates that were not fed ( n = 8) or fed colostrum ( n = 7) or formula ( n = 13) for 24 h after birth. Before birth, both colostrum and formula feeding resulted in marked increases in intestinal mass, brush-border enzyme activities, and plasma glucagon-like peptide 2 concentrations, to levels similar to those in NB colostrum-fed piglets. In contrast, NB formula-fed piglets showed reduced intestinal growth, decreased brush-border enzyme activities, and intestinal lesions, reflecting NEC. NB formula-fed pigs also showed impaired enterocyte endocytotic function and decreased antioxidative capacity, whereas brush-border enzyme mRNA levels were unaltered, relative to NB colostrum-fed pigs. Our results indicate that the feeding-induced growth and enzyme maturation of the immature intestine are not birth dependent. However, with a suboptimal diet (milk formula), factors related to preterm birth (e.g., microbial colonization and metabolic and endocrine changes) make the immature intestine sensitive to atrophy and development of NEC.

scholarly journals Histone H2B as a functionally important plasminogen receptor on macrophages

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3763-3772 ◽  
Author(s):  
Riku Das ◽  
Tim Burke ◽  
Edward F. Plow
Keyword(s):  
Binding Capacity ◽  
Peritoneal Macrophages ◽  
Blood Monocytes ◽  
Histone H2b ◽  
Cell Recruitment ◽  
Annexin 2 ◽  
Enhanced Expression ◽  
And Function ◽  
Mouse Peritoneal Macrophages

AbstractPlasminogen (Plg) facilitates inflammatory cell recruitment, a function that depends upon its binding to Plg receptors (Plg-Rs). However, the Plg-Rs that are critical for cell migration are not well defined. Three previously characterized Plg-Rs (α-enolase, annexin 2, and p11) and a recently identified Plg-R (histone H2B [H2B]) were assessed for their contribution to Plg binding and function on macrophages. Two murine macrophage cell lines (RAW 264.7 and J774A.1) and mouse peritoneal macrophages induced by thioglycollate were analyzed. All 4 Plg-Rs were present on the surface of these cells and showed enhanced expression on the thioglycollate-induced macrophages compared with peripheral blood monocytes. Using blocking Fab fragments to each Plg-R, H2B supported approximately 50% of the Plg binding capacity, whereas the other Plg-Rs contributed less than 25%. Anti-H2B Fab also demonstrated a major role of this Plg-R in plasmin generation and matrix invasion. When mice were treated intravenously with anti-H2B Fab, peritoneal macrophage recruitment in response to thioglycollate was reduced by approximately 45% at 24, 48, and 72 hours, with no effect on blood monocyte levels. Taken together, these data suggest that multiple Plg-Rs do contribute to Plg binding to macrophages, and among these, H2B plays a very prominent and functionally important role.

scholarly journals Increased Purinergic Responses Dependent on P2Y2 Receptors in Hepatocytes from CCl4-Treated Fibrotic Mice

2020 ◽  
Vol 21 (7) ◽  
pp. 2305 ◽  
Author(s):  
Erandi Velázquez-Miranda ◽  
Christian Molina-Aguilar ◽  
Adriana González-Gallardo ◽  
Olivia Vázquez-Martínez ◽  
Mauricio Díaz-Muñoz ◽  
...  
Keyword(s):  
Purinergic Signaling ◽  
P2y Receptors ◽  
Transcriptional Analysis ◽  
Zonal Distribution ◽  
P2y2 Receptors ◽  
Action Mechanisms ◽  
Ccl4 Administration ◽  
Enhanced Expression ◽  
And Function

Inflammatory and wound healing responses take place during liver damage, primarily in the parenchymal tissue. It is known that cellular injury elicits an activation of the purinergic signaling, mainly by the P2X7 receptor; however, the role of P2Y receptors in the onset of liver pathology such as fibrosis has not been explored. Hence, we used mice treated with the hepatotoxin CCl4 to implement a reversible model of liver fibrosis to evaluate the expression and function of the P2Y2 receptor (P2Y2R). Fibrotic livers showed an enhanced expression of P2Y2R that eliminated its zonal distribution. Hepatocytes from CCl4-treated mice showed an exacerbated ERK-phosphorylated response to the P2Y2R-specific agonist, UTP. Cell proliferation was also enhanced in the fibrotic livers. Hepatic transcriptional analysis by microarrays, upon CCl4 administration, showed that P2Y2 activation regulated diverse pathways, revealing complex action mechanisms. In conclusion, our data indicate that P2Y2R activation is involved in the onset of the fibrotic damage associated with the reversible phase of the hepatic damage promoted by CCl4.

scholarly journals Identification and function of adenosine A3 receptor in afferent arterioles

2015 ◽  
Vol 308 (9) ◽  
pp. F1020-F1025 ◽  
Author(s):  
Yan Lu ◽  
Rui Zhang ◽  
Ying Ge ◽  
Mattias Carlstrom ◽  
Shaohui Wang ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Receptor Activation ◽  
Mrna Levels ◽  
Afferent Arteriole ◽  
Ang Ii ◽  
Adenosine A3 Receptor ◽  
Afferent Arterioles ◽  
And Function ◽  
Dilatory Effect

Adenosine plays an important role in regulation of renal microcirculation. All receptors of adenosine, A1, A2A, A2B, and A3, have been found in the kidney. However, little is known about the location and function of the A3 receptor in the kidney. The present study determined the expression and role of A3 receptors in mediating the afferent arteriole (Af-Art) response and studied the interaction of A3 receptors with angiotensin II (ANG II), A1 and A2 receptors on the Af-Art. We found that the A3 receptor expressed in microdissected isolated Af-Art and the mRNA levels of A3 receptor were 59% of A1. In the isolated microperfused Af-Art, A3 receptor agonist IB-MECA did not have a constrictive effect. Activation of A3 receptor dilated the preconstricted Af-Art by norepinephrine and blunted the vasoconstrictive effect of both adenosine A1 receptor activation and ANG II on the Af-Art, respectively. Selective A2 receptor antagonist (both A2A and A2B) had no effect on A3 receptor agonist-induced vasodilation, indicating that the dilatory effect of A3 receptor activation is not mediated by activation of A2 receptor. We conclude that the A3 receptor is expressed in the Af-Art, and activation of the A3 receptor dilates the Af-Art.

Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats

2000 ◽  
Vol 278 (6) ◽  
pp. H2115-H2123 ◽  
Author(s):  
Erik Øie ◽  
Reidar Bjørnerheim ◽  
Ole Petter F. Clausen ◽  
Håvard Attramadal
Keyword(s):  
Cyclosporin A ◽  
Myocardial Hypertrophy ◽  
Plasma Renin ◽  
Mrna Levels ◽  
Tibial Length ◽  
And Function ◽  
Myocardial Gene Expression ◽  
Derivatives Of ◽  
Fractional Shortening

Calcineurin has recently been implicated as a mediator in the signaling pathways that transform intracellular calcium signals to the phenotype of myocardial hypertrophy. The present study was conducted to examine the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on myocardial hypertrophy and remodeling during congestive heart failure (CHF) in rats. After ligation of the left coronary artery, rats were randomized to treatment with CsA or vehicle for 14 days. Compared with vehicle, CsA substantially attenuated myocardial hypertrophy in the CHF rats as assessed by alterations in ventricular weight-to-tibial length ratios ( P < 0.05). Myocardial gene expression of skeletal α-actin was also reduced in the failing left ventricle (LV) after treatment with CsA ( P < 0.05), although the mRNA levels were still substantially elevated relative to those of sham rats. CsA-induced inhibition of compensatory myocardial hypertrophy in the CHF rats led to increased dilatation of the LV cavity and reduced fractional shortening and peak positive and negative first derivatives of LV pressure ( P < 0.05). Plasma renin and endothelin-1 levels were increased in the CHF-CsA rats, providing humoral cues of aggravated cardiac function. Thus this study supports a crucial role of calcineurin-dependent pathways in the mechanisms of compensatory myocardial hypertrophy during CHF. In addition, our data indicate that inhibition of compensatory myocardial hypertrophy exerts detrimental effects on cardiac remodeling and function after myocardial infarction.

Regulation of Intestinal Phosphate Transport II. Metabolic acidosis stimulates Na+-dependent phosphate absorption and expression of the Na+-Pi cotransporter NaPi-IIb in small intestine

2005 ◽  
Vol 288 (3) ◽  
pp. G501-G506 ◽  
Author(s):  
Annina Stauber ◽  
Tamara Radanovic ◽  
Gerti Stange ◽  
Heini Murer ◽  
Carsten A. Wagner ◽  
...  
Keyword(s):  
Small Intestine ◽  
Metabolic Acidosis ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Membrane Vesicles ◽  
Fractional Excretion ◽  
Phosphate Transport ◽  
The Body ◽  
Mrna Levels ◽  
Fractional Excretion Of Phosphate

During metabolic acidosis, Pi serves as an important buffer to remove protons from the body. Pi is released from bone together with carbonate buffering protons in blood. In addition, in the kidney, the fractional excretion of phosphate is increased allowing for the excretion of more acid equivalents in urine. The role of intestinal Pi absorption in providing Pi to buffer protons and compensating for loss from bone during metabolic acidosis has not been clarified yet. Inducing metabolic acidosis (NH4Cl in drinking water) for 2 or 7 days in mice increased urinary fractional Pi excretion twofold, whereas serum Pi levels were not altered. Na+-dependent Pi transport in the small intestine, however, was stimulated from 1.89 ± 3.22 to 40.72 ± 11.98 pmol/mg protein (2 days of NH4Cl) in brush-border membrane vesicles prepared from total small intestine. Similarly, the protein abundance of the Na+-dependent phosphate cotransporter NaPi-IIb in the brush-border membrane was increased 5.3-fold, whereas mRNA levels remained stable. According to immunohistochemistry and real-time PCR NaPi-IIb expression was found to be mainly confined to the ileum in the small intestine, and this distribution was not altered during metabolic acidosis. These results suggest that the stimulation of intestinal Pi absorption during metabolic acidosis may contribute to the buffering of acid equivalents by providing phosphate and may also help to prevent excessive liberation of phosphate from bone.

The aldo-keto reductase AKR1B7 coexpresses with renin without influencing renin production and secretion

2013 ◽  
Vol 304 (5) ◽  
pp. F578-F584 ◽  
Author(s):  
Katharina Machura ◽  
Elina Iankilevitch ◽  
Björn Neubauer ◽  
Franz Theuring ◽  
Armin Kurtz
Keyword(s):  
Enzyme Inhibitor ◽  
Plasma Renin ◽  
Mrna Levels ◽  
Wild Type ◽  
Mouse Vas Deferens ◽  
Salt Diet ◽  
Adult Kidney ◽  
Renin Mrna ◽  
And Function

On the basis of evidence that within the adult kidney, the aldo-keto reductase AKR1B7 (aldo-keto reductase family 1, member 7, also known as mouse vas deferens protein, MVDP) is selectively expressed in renin-producing cells, we aimed to define a possible role of AKR1B7 for the regulation and function of renin cells in the kidney. We could confirm colocalization and corecruitment of renin and of AKR1B7 in wild-type kidneys. Renin cells in AKR1B7-deficient kidneys showed normal morphology, numbers, and intrarenal distribution. Plasma renin concentration (PRC) and renin mRNA levels of AKR1B7-deficient mice were normal at standard chow and were lowered by a high-salt diet directly comparable to wild-type mice. Treatment with a low-salt diet in combination with an angiotensin-converting enzyme inhibitor strongly increased PRC and renin mRNA in a similar fashion both in AKR1B7-deficient and wild-type mice. Under this condition, we also observed a strong retrograde recruitment of renin-expressing cell along the preglomerular vessels, however, without a difference between AKR1B7-deficient and wild-type mice. The isolated perfused mouse kidney model was used to study the acute regulation of renin secretion by ANG II and by perfusion pressure. Regarding these parameters, no differences were observed between AKR1B7-deficient and wild-type kidneys. In summary, our data suggest that AKR1B7 is not of major relevance for the regulation of renin production and secretion in spite of its striking coregulation with renin expression.

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