Bicarbonate-sensitive calcification and lifespan of klotho-deficient mice

2016 ◽  
Vol 310 (1) ◽  
pp. F102-F108 ◽  
Author(s):  
Christina B. Leibrock ◽  
Jakob Voelkl ◽  
Ursula Kohlhofer ◽  
Leticia Quintanilla-Martinez ◽  
Makoto Kuro-o ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Mineral Metabolism ◽  
Plasma Concentrations ◽  
Extracellular Volume ◽  
Early Death ◽  
Volume Depletion ◽  
Deficient Diet ◽  
Plasma Aldosterone Concentration ◽  
Tissue Calcification ◽  
Deficient Mice

Klotho, a protein counteracting aging, is a powerful inhibitor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] formation and regulator of mineral metabolism. In klotho hypomorphic ( kl/kl) mice, excessive 1,25(OH)2D3 formation leads to hypercalcemia, hyperphosphatemia and vascular calcification, severe growth deficits, accelerated aging and early death. Kl/kl mice further suffer from extracellular volume depletion and hypotension, leading to the stimulation of antidiuretic hormone and aldosterone release. A vitamin D-deficient diet, restriction of dietary phosphate, inhibition of mineralocorticoid receptors with spironolactone, and dietary NaCl all extend the lifespan of kl/kl mice. Kl/kl mice suffer from acidosis. The present study explored whether replacement of tap drinking water by 150 mM NaHCO3 affects the growth, tissue calcification, and lifespan of kl/kl mice. As a result, NaHCO3 administration to kl/kl mice did not reverse the growth deficit but substantially decreased tissue calcification and significantly increased the average lifespan from 78 to 127 days. NaHCO3 did not significantly affect plasma concentrations of 1,25(OH)2D3 and Ca2+ but significantly decreased plasma phosphate concentration and plasma aldosterone concentration. The present study reveals a novel effect of bicarbonate, i.e., a favorable influence on vascular calcification and early death of klotho-deficient mice.

scholarly journals Hyperaldosteronism in Klotho-deficient mice

2010 ◽  
Vol 299 (5) ◽  
pp. F1171-F1177 ◽  
Author(s):  
Stephanie S. Fischer ◽  
Daniela S. Kempe ◽  
Christina B. Leibrock ◽  
Rexhep Rexhepaj ◽  
Balasaheb Siraskar ◽  
...  
Keyword(s):  
Vitamin D ◽  
Life Span ◽  
Ussing Chamber ◽  
Plasma Concentrations ◽  
Extracellular Volume ◽  
Present Observation ◽  
Deficient Diet ◽  
Plasma Urea ◽  
Renal Tubular ◽  
Deficient Mice

Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25-dihydroxyvitamin-D3 [1,25(OH)2D3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice ( klotho hm) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klotho hm mice and wild-type mice ( klotho+/+) were subjected to a normal (D+) or vitamin D-deficient (D−) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D−/+). At the age of 8 wk, body weight was significantly lower in klotho hmD+ mice than in klotho+/+D+ mice, klotho hmD− mice, and klotho hmD−/+ mice. Plasma concentrations of 1,25(OH)2D3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho hmD+ mice than in klotho+/+D+ mice. Plasma volume was significantly smaller in klotho hmD−/+ mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho hmD+ mice than in klotho+/+D+ mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca2+-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho hmD+ mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)2D3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.

PLASMA ALDOSTERONE CONCENTRATION IN ANEPHRIC CHILDREN

1974 ◽  
Vol 75 (3) ◽  
pp. 561-568 ◽  
Author(s):  
M. Birkhäuser ◽  
C. Godard ◽  
C. Loirat ◽  
M. B. Vallotton
Keyword(s):  
Serum Sodium ◽  
Plasma Cortisol ◽  
Potassium Concentration ◽  
Extracellular Volume ◽  
Sodium Concentration ◽  
Plasma Aldosterone ◽  
Volume Depletion ◽  
Plasma Aldosterone Concentration ◽  
Serum Potassium Concentration ◽  
Postural Changes

ABSTRACT The effect of extractive haemodialysis and of postural changes on the plasma aldosterone concentration has been studied in 5 anephric children. The plasma aldosterone concentration tended to be lower after haemodialysis in spite of the extracellular volume depletion induced. No regular response occurred after orthostatism. There was no correlation between the plasma aldosterone and the plasma cortisol or the serum sodium concentration. A weak positive correlation was found between the plasma aldosterone and serum potassium concentration, suggesting that potassium may play a major role in aldosterone regulation in the anephric state.

Modulation of jejunal ion and water absorption by endogenous angiotensin after dehydration

1984 ◽  
Vol 246 (6) ◽  
pp. G700-G709 ◽  
Author(s):  
N. R. Levens
Keyword(s):  
Water Absorption ◽  
Enzyme Inhibitor ◽  
Plasma Concentrations ◽  
Extracellular Volume ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Transport Processes ◽  
Transepithelial Transport ◽  
Volume Depletion ◽  
Jejunal Absorption

In the pentobarbital sodium-anesthetized rat, dehydration for 24 h increased ion and water absorption from the jejunum. Dehydration also elevated plasma concentrations of angiotensin peptides and plasma renin activity but did not significantly alter plasma aldosterone concentrations. Infusion of tyramine, norepinephrine, and angiotensin II (AII) also stimulated jejunal absorption in a manner similar to dehydration. The elevation of jejunal absorption in response to dehydration is totally inhibited by the converting enzyme inhibitor captopril and the angiotensin receptor antagonist [lle7]AIII. Thus, increased jejunal absorption following dehydration is mediated by the renin-angiotensin system and is not secondary to either aldosterone or to antidiuretic hormone release. Further experiments demonstrated that the increase in jejunal absorption in response to dehydration was unaffected by propranolol but was totally abolished by phentolamine, prazosin, and peripheral sympathectomy. It is proposed that AII stimulates jejunal absorption by enhancing transepithelial transport processes and/or by altering the balance of Starling forces governing fluid absorption across enteric capillaries. Angiotensin thus appears to be a physiologically important mediator of jejunal absorption in states characterized by extracellular volume depletion.

INZ ‐701 prevents ectopic tissue calcification and restores bone architecture and growth in ENPP1 deficient mice

2021 ◽  
Author(s):  
Zhiliang Cheng ◽  
Kevin O'Brien ◽  
Jennifer Howe ◽  
Caitlin Sullivan ◽  
Denis Schrier ◽  
...  
Keyword(s):  
Bone Architecture ◽  
Tissue Calcification ◽  
Ectopic Tissue ◽  
Deficient Mice

Angiotensin II Mediates Increased Small Intestinal Fluid Absorption with Extracellular Volume Depletion in the Rat*

Endocrinology ◽  
1984 ◽  
Vol 114 (5) ◽  
pp. 1692-1701 ◽  
Author(s):  
NIGEL R. LEVENS ◽  
SHIELA P. MARRISCOTTI ◽  
MICHAEL J. PEACH ◽  
KENNETH A. MUNDAY ◽  
ROBERT M. CAREY
Keyword(s):  
Angiotensin Ii ◽  
Extracellular Volume ◽  
Intestinal Fluid ◽  
Fluid Absorption ◽  
Volume Depletion ◽  
Small Intestinal

scholarly journals Hyponatremia in visceral leishmaniasis

2010 ◽  
Vol 52 (5) ◽  
pp. 253-258 ◽  
Author(s):  
Frederico A. Lima Verde ◽  
Francisco A.A. Lima Verde ◽  
Francisco José V. Veronese ◽  
Augusto S. Neto ◽  
Galdino Fuc ◽  
...  
Keyword(s):  
Uric Acid ◽  
Visceral Leishmaniasis ◽  
Antidiuretic Hormone ◽  
Hormone Secretion ◽  
Extracellular Volume ◽  
Urine Osmolality ◽  
Control Group ◽  
Volume Depletion ◽  
Antidiuretic Hormone Secretion ◽  
Kala Azar

There are few reports linking hyponatremia and visceral leishmaniasis (kala-azar). This is a study of 55 consecutive kala-azar patients and 20 normal individuals as a control group. Hyponatremia and serum hypo-osmolality were detected in 100% of kala-azar patients. High first morning urine osmolality (750.0 ± 52.0 vs. 894.5 ± 30.0mOsm/kg H2O, p < 0.05), and high 24-hour urine osmolality (426.0 ± 167.0 vs. 514.6 ± 132.0 mOsm/kg H2O, p < 0.05) demonstrated persistent antidiuretic hormone secretion. Urinary sodium was high (82.3 ± 44.2 vs.110.3 ± 34.7 mEq/L, p < 0.05). Low seric uric acid occurred in 61.8% of patients and increased fractional urinary uric acid excretion was detected in 74.5% of them. Increased glomerular filtration rate was present in 25.4% of patients. There was no evidence of extracellular volume depletion. Normal plasma ADH levels were observed in kala-azar patients. No endocrine or renal dysfunction was detected. It is possible that most hyponatremic kala-azar patients present the syndrome of inappropriate antidiuretic hormone secretion.

scholarly journals Complement factor D is linked to platelet activation in human and rodent sepsis

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
O. Sommerfeld ◽  
K. Dahlke ◽  
M. Sossdorf ◽  
R. A. Claus ◽  
A. Scherag ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Physiological Function ◽  
Plasma Concentrations ◽  
Cecal Ligation ◽  
Clinical Importance ◽  
Surface Expression ◽  
Antiplatelet Drugs ◽  
Complement Factor ◽  
Wild Type ◽  
Deficient Mice

Abstract Background The complement factor D (CFD) exerts a regulatory role during infection. However, its physiological function in coagulopathy and its impact on the course of an infection remains unclear. Materials Wild-type and CFD-deficient mice (n = 91) were subjected to cecal ligation and puncture to induce sepsis. At several time points, markers of coagulation and the host-immune response were determined. Furthermore, in patients (n = 79) with sepsis or SIRS, CFD levels were related to clinical characteristics, use of antiplatelet drugs and outcome. Results Septic CFD-deficient mice displayed higher TAT complexes (p = 0.02), impaired maximal clot firmness, but no relevant platelet drop and reduced GPIIb/IIIa surface expression on platelets (p = 0.03) compared to septic wild-type mice. In humans, higher CFD levels (non-survivors, 5.0 µg/ml to survivors, 3.6 µg/ml; p = 0.015) were associated with organ failure (SOFA score: r = 0.33; p = 0.003) and mortality (75% percentile, 61.1% to 25% percentile, 26.3%). CFD level was lower in patients with antiplatelet drugs (4.5–5.3 µg/ml) than in patients without. Conclusion In mice, CFD is linked to pronounced platelet activation, depicted by higher GPIIb/IIIa surface expression in wild-type mice. This might be of clinical importance since high CFD plasma concentrations were also associated with increased mortality in sepsis patients.

scholarly journals Vascular calcification has a role in acute non-renal phosphate clearance

2020 ◽  
Author(s):  
Mandy E Turner ◽  
Austin P Lansing ◽  
Paul S Jeronimo ◽  
Lok Hang Lee ◽  
Bruno A Svajger ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Phosphate Uptake ◽  
Mineral Metabolism ◽  
Extracellular Fluid ◽  
Systemic Response ◽  
Phosphate Homeostasis ◽  
Rat Models ◽  
Oral Consumption ◽  
Circulating Levels ◽  
Systemic Disposition

AbstractRationaleNon-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. Following oral consumption of phosphate, circulating levels normalize long before urinary excretion has been completed. This process is especially relevant in the setting of chronic kidney disease (CKD), where phosphate exposure is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated dysregulation of mineral metabolism exacerbates pathological accumulation of phosphate causing vascular calcification (VC).ObjectiveDetermine whether the systemic response to acute phosphate challenges is altered by the development and progression of VC.Methods/ResultsAcute circulating and tissue deposition of an acute phosphate challenge was assessed in two rat models of VC using radio-labelled phosphate tracer. In an adenine-induced model of CKD with VC, animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration and the discordant deposition could be traced to the calcifying vasculature. In a non-CKD model of VC, VC was induced with 0.5ug/kg calcitriol and then withdrawn. The radio-labelled phosphate challenge was given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. The new transport to the calcifying vasculature correlates to the pre-existing burden of calcification, and can be substantially attenuated by removing the stimulus for calcification. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate.ConclusionsOur data indicate that calcifying arteries alter the systemic disposition of a phosphate challenge and acutely deposit substantial phosphate. This study supports the importance of diet as it relates to acute fluctuations of circulating phosphate and the importance of bioavailability and meal-to-meal management in CKD patients as a mediator of cardiovascular risk.

Postnatal adrenalectomy impairs urinary concentrating ability by increased COX-2 and leads to renal medullary injury

2007 ◽  
Vol 293 (3) ◽  
pp. F780-F789 ◽  
Author(s):  
Jane Stubbe ◽  
Kirsten Madsen ◽  
Finn T. Nielsen ◽  
Rasmus K. Bonde ◽  
Ole Skøtt ◽  
...  
Keyword(s):  
Weight Gain ◽  
Extracellular Volume ◽  
Renal Medulla ◽  
Postnatal Period ◽  
Sham Operation ◽  
Volume Depletion ◽  
Rat Pups ◽  
Cox 2 ◽  
Urinary Concentrating Ability ◽  
Urine Concentrating Ability

We hypothesized that aldosterone promotes development of the renal medulla in the postnatal period and that cyclooxygenase-2 (COX-2) activity contributes to renal dysfunction after impaired aldosterone signaling. To test these hypotheses, rat pups underwent either sham operation or adrenalectomy at postnatal day 10. Adrenalectomized rats were divided into no steroid substitution (ADX), corticosterone replacement (ADX-C), and corticosterone and DOCA substitution (ADX-CD) groups that received subcutaneous pellets with steroids. Without replacement, pups failed to thrive and exhibited impaired urinary-concentrating ability. The renal medulla was significantly smaller, and the medullary interstitial osmolality was lower in the ADX group, whereas COX-2 and PGE2 tissue levels were significantly elevated compared with levels shown in sham animals. Substitution with DOCA and corticosterone corrected these changes, whereas corticosterone replacement alone improved survival but not weight gain and urinary-concentrating ability. Administration of a COX-2 inhibitor to ADX rats (parecoxib, 5 mg·kg−1·day−1, days 17–20) increased weight gain, urinary-concentrating ability, and papillary osmolality. After fluid deprivation, parecoxib attenuated weight loss and the increase in plasma Na+ concentration and osmolality. It is concluded that mineralocorticoid is required for normal postnatal development of the renal medulla. COX-2 contributes to impaired urine-concentrating ability, NaCl loss, and extracellular volume depletion in postnatal mineralocorticoid deficiency.

scholarly journals Phosphatidylcholine transfer protein/StarD2 promotes microvesicular steatosis and liver injury in murine experimental steatohepatitis

2017 ◽  
Vol 313 (1) ◽  
pp. G50-G61 ◽  
Author(s):  
Hayley T. Nicholls ◽  
Jason L. Hornick ◽  
David E. Cohen
Keyword(s):  
Liver Injury ◽  
Lipid Droplets ◽  
Plasma Concentrations ◽  
Fibroblast Growth Factor 21 ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Pathogenic Role ◽  
Deficient Diet ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein

Mice fed a methionine- and choline-deficient (MCD) diet develop steatohepatitis that recapitulates key features of nonalcoholic steatohepatitis (NASH) in humans. Phosphatidylcholine is the most abundant phospholipid in the surfactant monolayer that coats and stabilizes lipid droplets within cells, and choline is required for its major biosynthetic pathway. Phosphatidylcholine-transfer protein (PC-TP), which exchanges phosphatidylcholines among membranes, is enriched in hepatocytes. PC-TP also regulates fatty acid metabolism through interactions with thioesterase superfamily member 2. We investigated the contribution of PC-TP to steatohepatitis induced by the MCD diet. Pctp−/− and wild-type control mice were fed the MCD diet for 5 wk and were then euthanized for histopathologic and biochemical analyses, as well as determinations of mRNA and protein expression. Whereas all mice developed steatohepatitis, plasma alanine aminotransferase and aspartate aminotransferase activities were only elevated in wild-type mice, indicating that Pctp−/− mice were protected from MCD diet-induced hepatocellular injury. Reduced hepatotoxicity due to the MCD diet in the absence of PC-TP expression was further evidenced by decreased activation of c-Jun and reduced plasma concentrations of fibroblast growth factor 21. Despite similar total hepatic concentrations of phosphatidylcholines and other lipids, the relative abundance of microvesicular lipid droplets within hepatocytes was reduced in Pctp−/− mice. Considering that the formation of larger lipid droplets may serve to protect against lipotoxicity in NASH, our findings suggest a pathogenic role for PC-TP that could be targeted in the management of this condition. NEW & NOTEWORTHY Phosphatidylcholine-transfer protein (PC-TP) is a highly specific phosphatidylcholine-binding protein that we previously showed to regulate hepatocellular nutrient metabolism through its interacting partner thioesterase superfamily member 2 (Them2). This study identifies a pathogenic role for PC-TP, independent of Them2, in the methionine- and choline-deficient diet model of experimental steatohepatitis. Our current observations suggest that PC-TP promotes liver injury by mediating the intermembrane transfer of phosphatidylcholines, thus stabilizing more pathogenic microvesicular lipid droplets.

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