Abnormal water metabolism in mice lacking the type 1A receptor for ANG II

2000 ◽  
Vol 278 (1) ◽  
pp. F75-F82 ◽  
Author(s):  
Michael I. Oliverio ◽  
Marielle Delnomdedieu ◽  
Christopher F. Best ◽  
Ping Li ◽  
Mariana Morris ◽  
...  
Keyword(s):  
Water Deprivation ◽  
Critical Role ◽  
Urine Concentration ◽  
Urinary Concentration ◽  
Structural Abnormality ◽  
Ang Ii ◽  
Wild Type ◽  
Water Metabolism ◽  
Water Excretion ◽  
Plasma Vasopressin

Mice lacking AT1Areceptors for ANG II have a defect in urinary concentration manifested by an inability to increase urinary osmolality to levels seen in controls after thirsting. This defect results in extreme serum hypertonicity during water deprivation. In the basal state, plasma vasopressin levels are similar in wild-type controls and Agtr1a −/− mice. Plasma vasopressin levels increase normally in the AT1A receptor-deficient mice after 24 h of water deprivation, suggesting that the defect in urine concentration is intrinsic to the kidney. Using magnetic resonance microscopy, we find that the absence of AT1A receptors is associated with a modest reduction in the distance from the kidney surface to the tip of the papilla. However, this structural abnormality seems to play little role in the urinary concentrating defect in Agtr1a −/− mice since the impairment is largely reproduced in wild-type mice by treatment with an AT1-receptor antagonist. These studies demonstrate a critical role for the AT1A receptor in maintaining inner medullary structures in the kidney and in regulating renal water excretion.

Long-term treatment with cyclosporine decreases aquaporins and urea transporters in the rat kidney

2004 ◽  
Vol 287 (1) ◽  
pp. F139-F151 ◽  
Author(s):  
Sun-Woo Lim ◽  
Can Li ◽  
Bo-Kyung Sun ◽  
Ki-Hwan Han ◽  
Wan-Young Kim ◽  
...  
Keyword(s):  
Urine Volume ◽  
Urine Concentration ◽  
Urinary Concentration ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Plasma Vasopressin ◽  
Fractional Excretion Of Sodium ◽  
Long Term Treatment ◽  
Rat Kidneys

The aim of this study was to evaluate the long-term effects of cyclosporine (CsA) treatment on urinary concentration ability. Rats were treated daily for 4 wk with vehicle (VH; olive oil, 1 ml/kg sc) or CsA (15 mg/kg sc). The influence of CsA on the kidney's ability to concentrate urine was evaluated using functional parameters and expression of aquaporins (AQP1–4) and of urea transporters (UT-A-1–3, and UT-B). Plasma vasopressin levels and the associated signal pathway were evaluated, and the effect of vasopressin infusion on urine concentration was observed in VH- and CsA-treated rats. Toxic effects of CsA on tubular cells in the medulla as well as the cortex were evaluated with aldose reductase (AR), Na-K-ATPase-α1 expression, and by determining the number of terminal transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells. Long-term CsA treatment increased urine volume and fractional excretion of sodium and decreased urine osmolality and free-water reabsorption compared with VH-treated rats. These functional changes were accompanied by decreases in the expression of AQP (1–4) and UT (UT-A2, -A3, and UT-B), although there was no change in AQP2 in the cortex and outer medulla and UT-A1 in the inner medulla (IM). Plasma vasopressin levels were not significantly different between two groups, but infusion of vasopressin restored CsA-induced impairment of urine concentration. cAMP levels and Gsα protein expression were significantly reduced in CsA-treated rat kidneys compared with VH-treated rat kidneys. CsA treatment decreased the expression of AR and Na-K-ATPase-α1 and increased the number of TUNEL-positive renal tubular cells in both the cortex and medulla. Moreover, the number of TUNEL-positive cells correlated with AQP2 or UT-A3) expression within the IM. In conclusion, CsA treatment impairs urine-concentrating ability by decreasing AQP and UT expression. Apoptotic cell death within the IM at least partially accounts for the CsA-induced urinary concentration defect.

scholarly journals Activation of ENaC by AVP contributes to the urinary concentrating mechanism and dilution of plasma

2015 ◽  
Vol 308 (3) ◽  
pp. F237-F243 ◽  
Author(s):  
Elena Mironova ◽  
Yu Chen ◽  
Alan C. Pao ◽  
Karl P. Roos ◽  
Donald E. Kohan ◽  
...  
Keyword(s):  
Tap Water ◽  
Critical Role ◽  
Urine Osmolality ◽  
Urine Concentration ◽  
Urinary Concentration ◽  
Nacl Solution ◽  
Urinary Osmolality ◽  
Water Homeostasis ◽  
Blood Pressure Homeostasis ◽  
Stimulation Of

Arginine vasopressin (AVP) activates the epithelial Na+channel (ENaC). The physiological significance of this activation is unknown. The present study tested if activation of ENaC contributes to AVP-sensitive urinary concentration. Consumption of a 3% NaCl solution induced hypernatremia and plasma hypertonicity in mice. Plasma AVP concentration and urine osmolality increased in hypernatremic mice in an attempt to compensate for increases in plasma tonicity. ENaC activity was elevated in mice that consumed 3% NaCl solution compared with mice that consumed a diet enriched in Na+with ad libitum tap water; the latter diet does not cause hypernatremia. To determine whether the increase in ENaC activity in mice that consumed 3% NaCl solution served to compensate for hypernatremia, mice were treated with the ENaC inhibitor benzamil. Coadministration of benzamil with 3% NaCl solution decreased urinary osmolality and increased urine flow so that urinary Na+excretion increased with no effect on urinary Na+concentration. This decrease in urinary concentration further increased plasma Na+concentration, osmolality, and AVP concentration in these already hypernatremic mice. Benzamil similarly compromised urinary concentration in water-deprived mice and in mice treated with desmopressin. These results demonstrate that stimulation of ENaC by AVP plays a critical role in water homeostasis by facilitating urinary concentration, which can compensate for hypernatremia or exacerbate hyponatremia. The present findings are consistent with ENaC in addition to serving as a final effector of the renin-angiotensin-aldosterone system and blood pressure homeostasis, also playing a key role in water homeostasis by regulating urine concentration and dilution of plasma.

scholarly journals Manganese promotes intracellular accumulation of AQP2 via modulating F-actin polymerization and reduces urinary concentration in mice

2018 ◽  
Vol 314 (2) ◽  
pp. F306-F316 ◽  
Author(s):  
Lei Lei ◽  
Ming Huang ◽  
Limin Su ◽  
Dongping Xie ◽  
Fahmy A. Mamuya ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Cultured Cells ◽  
Critical Role ◽  
Water Channel ◽  
Urine Concentration ◽  
Urinary Concentration ◽  
Intracellular Accumulation ◽  
Rhoa Activity ◽  
Cytoskeletal Dynamics

Aquaporin-2 (AQP2) is a water channel protein expressed in principal cells (PCs) of the kidney collecting ducts (CDs) and plays a critical role in mediating water reabsorption and urine concentration. AQP2 undergoes both regulated trafficking mediated by vasopressin (VP) and constitutive recycling, which is independent of VP. For both pathways, actin cytoskeletal dynamics is a key determinant of AQP2 trafficking. We report here that manganese chloride (MnCl2) is a novel and potent regulator of AQP2 trafficking in cultured cells and in the kidney. MnCl2 treatment promoted internalization and intracellular accumulation of AQP2. The effect of MnCl2 on the intracellular accumulation of AQP2 was associated with activation of RhoA and actin polymerization without modification of AQP2 phosphorylation. Although the level of total and phosphorylated AQP2 did not change, MnCl2 treatment impeded VP-induced phosphorylation of AQP2 at its serine-256, -264, and -269 residues and dephosphorylation at serine 261. In addition, MnCl2 significantly promoted F-actin polymerization along with downregulation of RhoA activity and prevented VP-induced membrane accumulation of AQP2. Finally, MnCl2 treatment in mice resulted in significant polyuria and reduced urinary concentration, likely due to intracellular relocation of AQP2 in the PCs of kidney CDs. More importantly, the reduced urinary concentration caused by MnCl2 treatment in animals was not corrected by VP. In summary, our study identified a novel effect of MnCl2 on AQP2 trafficking through modifying RhoA activity and actin polymerization and uncovered its potent impact on water diuresis in vivo.

Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins

2002 ◽  
Vol 283 (3) ◽  
pp. F517-F524 ◽  
Author(s):  
Janet D. Klein ◽  
D. Le Quach ◽  
Justin M. Cole ◽  
Kevin Disher ◽  
Anne K. Mongiu ◽  
...  
Keyword(s):  
Urine Concentration ◽  
Transport Proteins ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Wild Type ◽  
Outer Medulla ◽  
Aquaporin 1 ◽  
Ace Activity ◽  
Tissue Angiotensin ◽  
Concentrating Defect

ACE.2 mice lack all tissue angiotensin-converting enzyme (ACE) but have 33% of normal plasma ACE activity. They exhibit the urine-concentrating defect and hyperkalemia present in mice that lack all ACE, but in contrast to the complete knockout, ACE.2 mice have normal medullary histology and creatinine clearance. To explore the urine-concentrating defect in ACE.2 mice, renal medullary transport proteins were analyzed using Western blot analysis. In the inner medulla, UT-A1, ClC-K1, and aquaporin-1 (AQP1) were significantly reduced to 28 ± 5, 6 ± 6, and 39 ± 5% of the level in wild-type mice, respectively, whereas AQP2 and UT-B were unchanged. In the outer medulla, Na+-K+-2Cl− cotransporter (NKCC2/BSC1) and AQP1 were significantly reduced to 56 ± 11 and 29 ± 6%, respectively, whereas Na+-K+-ATPase, UT-A2, UT-B, and AQP2 were unchanged, and renal outer medullary potassium channel was significantly increased to 711 ± 187% of the level in wild-type mice. The abnormal expression of these transporters was similar in ACE.2 mice backcrossed onto a C57BL/6 or a Swiss background and was not rescued by ANG II infusion. We conclude that the urine-concentrating defect in ACE.2 mice is associated with, and may result from, downregulation of some or all of these key urea, salt, and water transport proteins.

scholarly journals AT1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT1a receptor-deficient mice

2012 ◽  
Vol 303 (5) ◽  
pp. F746-F756 ◽  
Author(s):  
Xiao C. Li ◽  
Yuan Shao ◽  
Jia L. Zhuo
Keyword(s):  
Adenylyl Cyclase ◽  
Water Deprivation ◽  
Urine Osmolality ◽  
Urine Concentration ◽  
Ang Ii ◽  
Receptor Signaling ◽  
Urine Excretion ◽  
Lower Systolic Blood Pressure ◽  
At1a Receptor ◽  
Total Lysate

It is well recognized that ANG II interacts with arginine vasopressin (AVP) to regulate water reabsorption and urine concentration in the kidney. The present study used ANG II type 1a (AT1a) receptor-deficient (Agtr1a−/−) mice to test the hypothesis that AT1a receptor signaling is required for basal and water deprivation-induced urine concentration in the renal medulla. Eight groups of wild-type (WT) and Agtr1a−/− mice were treated with or without 24-h water deprivation and 1-desamino-8-d-AVP (DDAVP; 100 ng/h ip) for 2 wk or with losartan (10 mg/kg ip) during water deprivation. Under basal conditions, Agtr1a−/− mice had lower systolic blood pressure ( P < 0.01), greater than threefold higher 24-h urine excretion (WT mice: 1.3 ± 0.1 ml vs. Agtr1a−/− mice: 5.9 ± 0.7 ml, P < 0.01), and markedly decreased urine osmolality (WT mice: 1,834 ± 86 mosM/kg vs. Agtr1a−/− mice: 843 ± 170 mosM/kg, P < 0.01), without significant changes in 24-h urinary Na+ excretion. These responses in Agtr1a−/− mice were associated with lower basal plasma AVP (WT mice: 105 ± 8 pg/ml vs. Agtr1a−/− mice: 67 ± 6 pg/ml, P < 0.01) and decreases in total lysate and membrane aquaporin-2 (AQP2; 48.6 ± 7% of WT mice, P < 0.001) and adenylyl cyclase isoform III (55.6 ± 8% of WT mice, P < 0.01) proteins. Although 24-h water deprivation increased plasma AVP to the same levels in both strains, 24-h urine excretion was still higher, whereas urine osmolality remained lower, in Agtr1a−/− mice ( P < 0.01). Water deprivation increased total lysate AQP2 proteins in the inner medulla but had no effect on adenylyl cyclase III, phosphorylated MAPK ERK1/2, and membrane AQP2 proteins in Agtr1a−/− mice. Furthermore, infusion of DDAVP for 2 wk was unable to correct the urine-concentrating defects in Agtr1a−/− mice. These results demonstrate that AT1a receptor-mediated ANG II signaling is required to maintain tonic AVP release and regulate V2 receptor-mediated responses to water deprivation in the inner medulla.

scholarly journals Water Metabolism

1977 ◽  
Vol 5 (4) ◽  
pp. 295-304 ◽  
Author(s):  
P. J. Phillips
Keyword(s):  
Antidiuretic Hormone ◽  
Collecting Duct ◽  
Hormone Secretion ◽  
Distal Tubule ◽  
Urine Concentration ◽  
Urinary Concentration ◽  
Osmotic Gradient ◽  
Water Metabolism ◽  
Antidiuretic Hormone Secretion ◽  
Osmotic Stimuli

Total body water is finely regulated and controls of intake and output are maximally activated by small osmotic changes. Sensors in the hypothalamus invoke the fluid repletion or depletion reactions through changes in thirst, urine concentration and solute intake. Antidiuretic hormone controls urinary concentration and is released mainly in response to osmotic stimuli. However, the threshold and sensitivity of this response are affected by non osmotic stimuli. Urine concentration varies in response to antidiuretic hormone only if the distal tubule, collecting duct and hypertonic medullary interstitum are intact. The capacity to conserve or excrete water depends on the osmolar load and an efficient urinary concentrating or diluting mechanism. Disorders of thirst are uncommon and often associated with abnormal antidiuretic hormone secretion. Disorders of urine concentration and dilution are common in illness and reflect abnormalities of antidiuretic hormone secretion or the renal mechanisms generating the osmotic gradient. When urine concentrating capacity is impaired ( true or nephrogenic diabetes insipidus) water depletion occurs only when thirst fails or access to water is denied. When urine diluting ability is impaired, water excess occurs when the osmolar load and minimum urinary osmolality generated are inadequate for the fluid intake. Hyper-osmolality and hypo-osmolality are usually caused by abnormal water metabolism although they may be associated with abnormalities of solute metabolism. The various clinical syndromes are determined by the primary disease, and the associated fluid volume and osmolar abnormalities.

scholarly journals Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Peipei Li ◽  
Zongzhuang Wen ◽  
Guangkai Zhang ◽  
Aizhen Zhang ◽  
Xiaolong Fu ◽  
...  
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Critical Role ◽  
Kinase Domain ◽  
Mutant Mice ◽  
Structural Abnormality ◽  
Wild Type ◽  
Cell Degeneration ◽  
Cochlear Hair Cells

Myo3a is expressed in cochlear hair cells and retinal cells and is responsible for human recessive hereditary nonsyndromic deafness (DFNB30). To investigate the mechanism of DFNB30-type deafness, we established a mouse model of Myo3a kinase domain Y137C mutation by using CRISPR/Cas9 system. No difference in hearing between 2-month-old Myo3a mutant mice and wild-type mice was observed. The hearing threshold of the ≥6-month-old mutant mice was significantly elevated compared with that of the wild-type mice. We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months. We also found structural abnormality in the cochlear hair cell stereocilia. Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a. This mouse line is an excellent model for studying DFNB30-type deafness in humans.

Abstract 271: NF-kB Mediated Modulation of mir-23b/-130a-axis is Critical for Cardiac Remodeling

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Li Li
Keyword(s):  
Cross Talk ◽  
Cardiac Remodeling ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Critical Role ◽  
Left Ventricular ◽  
Ang Ii ◽  
Wild Type ◽  
Mrna Targets ◽  
Adverse Remodeling

Cardiac remodeling is a process that alters structural and functional determinants of myocardium in response to hemodynamic stress resulted in left ventricular hypertrophy, fibrosis leading to heart failure. Pressure overload that induces cardiac remodeling involves both cardiomyocytes (CM) and cardiac fibroblasts (CF) cross-talk for the development of adverse remodeling. The miRNAs are a new class of post-transcriptional regulator capable of repressing gene expression by base pairing to the 3' UTR of mRNA targets; involved in diverse cardiac diseases. However, the function of miRNAs in cellular cross-talk leading to cardiac remodeling remains elusive. Previously, we showed that inhibition of NF-kB prevents cardiac remodeling; however, NF-κB mediated miRNAs’ role in cardiac remodeling remains elusive. We will test the hypothesis that NF-κB dependent miR-23b/-130a is a pathogenic niche regulating the cardiac remodeling; and inhibition of miR-23b/-130a abrogates the adverse remodeling by restoring PPARg-PTEN-axis. We have identified a panel of novel dysregulated miRNAs in the left ventricle of wild type mice subjected to thoracic aortic constriction (TAC). The dysregulated miRNAs were restored in cardiac-specific IκBα triple-mutant transgenic mice (3M) subjected to TAC indicated NF-kB dependent regulation. We observed that miR-130a and miR-23b were significantly upregulated in TAC and Ang II infusion and were inhibited in 3M-TAC mice. We identified PPARg-PTEN-axis, a bona-fide target for miR-23b/-130a after unbiased in vitro screening. Inhibition of NF-kB normalized miR-23b/-130a expression and the target genes in Ang II and TGFb1 stimulated CM and CF. Inhibition of miR-130a showed reduction of cell sizes in CM and decrease cellular proliferation in CF indicated a cellular cross-talk. The in vivo inhibition of miR-130a in wild-type mice after Ang II infusion significantly reduced cardiac remodeling, restoring PPARg-PTEN level and improved cardiac function. Our findings provide evidence that miR-23b/-130a displays a critical role in the pathogenesis of cardiac remodeling. We conclude that miR-23b/-130a could be a triggering factor in cardiac remodeling and providing new mechanistic information for therapeutic benefit.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

scholarly journals CHROMOSOMAL BASIS OF THE MEROZYGOSITY IN A PARTIALLY DIPLOID MUTANT OF PNEUMOCOCCUS

Genetics ◽  
1975 ◽  
Vol 80 (4) ◽  
pp. 667-678
Author(s):  
Mary Lee S Ledbetter ◽  
Rollin D Hotchkiss
Keyword(s):  
High Efficiency ◽  
Point Mutations ◽  
Resistant Mutant ◽  
Chromosomal Marker ◽  
Structural Abnormality ◽  
C Cells ◽  
Wild Type ◽  
Chromosomal Locus ◽  
Low Efficiency ◽  
Derivatives Of

ABSTRACT A sulfonamide-resistant mutant of pneumococcus, sulr-c, displays a genetic instability, regularly segregating to wild type. DNA extracts of derivatives of the strain possess transforming activities for both the mutant and wild-type alleles, establishing that the strain is a partial diploid. The linkage of sulr-c to strr-61, a stable chromosomal marker, was established, thus defining a chromosomal locus for sulr-c. DNA isolated from sulr-c cells transforms two mutant recipient strains at the same low efficiency as it does a wild-type recipient, although the mutant property of these strains makes them capable of integrating classical "low-efficiency" donor markers equally as efficiently as "high efficiency" markers. Hence sulr-c must have a different basis for its low efficiency than do classical low efficiency point mutations. We suggest that the DNA in the region of the sulr-c mutation has a structural abnormality which leads both to its frequent segregation during growth and its difficulty in efficiently mediating genetic transformation.

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