Decrease In Urinary Concentration Research Articles

Chronic aldosterone administration alters aquaporin expression and localization in the murine kidney

The steroid hormone aldosterone is an important regulator of fluid balance and electrolyte homeostasis. While acute aldosterone signaling is canonically associated with fluid retention due to its role in promoting sodium reabsorption through ENaC in the distal nephron, chronic aldosterone exposure has been shown to exacerbate urine production in a rat model of diabetes insipidus through its actions on aquaporin 2 (AQP2) localization and expression. In our studies, we aimed to characterize not only the effect of chronic aldosterone administration on AQP2 expression and localization, but also its effect on the basolateral water channels, AQP3 and AQP4. Given the large urinary output we observed in our animals following chronic aldosterone treatments, we hypothesized all three of these channels would show reduced expression.Aldosterone was administered to male C57Bl/6 mice at a dose of 200 μg/kg/day for 28 days via subcutaneous minipumps. Aldosterone treatment caused a significant diuresis as compared to control animals by day 15 (Ctl 4.8 ± 1.6 ml; Aldo 8.4 ± 2.4 ml), and this difference persisted for the remainder of the experiment. Mice given aldosterone also consumed more water as compared to their control counterparts (Ctl 4.0 ± 1.2 ml; Aldo 9.6 ± 2.3 ml). Urine osmolality was measured by freeze-point depression, with a significant decrease in urinary concentration being noted during the daytime by day 4 (Ctl 1219.8 ± 473.4 mOsm/kg; Aldo 638.8 ± 143.8 mOsm/kg) and during the night by day 17 (Ctl 905.3 ± 175.1 mOsm/kg; Aldo 522.2 ± 127.3 mOsm/kg). At the end of the 28 days of aldosterone administration, mice receiving aldosterone had a higher whole blood [Na + ] (Ctl 146 ± 1.9mmol/l; Aldo 152 ± 1.3mmol/l) and lower whole blood [K+] (Ctl 4.8 ± 0.56mmol/l; Aldo 3.0 ± 0.34mmol/l) as measured by iSTAT cartridge with terminal cardiac blood draw.Kidneys were examined by Western blot and immunofluorescent staining for expression and localization of the three AQPs. AQP2 expression decreased after both 14 and 28 days of aldosterone administration, with line scan analysis showing a decreased signal present at the apical membrane. AQP3 expression was decreased in the basolateral membranes of principal cells within the cortex of the kidney but increased in cells within the inner medulla after 28 days of aldosterone. AQP4 levels were significantly increased in AQP2-positive cells of the inner stripe of the outer medulla and the inner medulla, suggesting that this channel may be upregulated to compensate for changes in the other two aquaporins. Potassium supplementation to separate the effects of aldosterone administration from hypokalemia did not rescue the expression of these channels.Overall, our studies reveal that chronic aldosterone administration in healthy mice leads to polyuria and polydipsia, with decreased apical expression of AQP2 and variable changes in AQP3 and AQP4 dependent on location within in the kidney. This study was funded by NIH grants R01 DK130901 (to SS), R01 HL147818 and R01 DK129285 (to TRK), and P30 DK079307 (the Pittsburgh Center for Kidney Research). SMM was supported by T32 DK061296, T32 DK007052, and a grant from Relypsa. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009-2017.

During the past two decades human exposure to bisphenol A (BPA) and phthalates such as di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP) and di-(2-ethyl-hexyl) phthalate (DEHP) has received substantial interest due to widespread population exposures and potential endocrine disrupting effects. Therefore, these chemicals have gradually been restricted and phased out through legislation. However, humans are still exposed to a wide range of other less studied phthalates, phthalate substitutes and BPA analogues as well as other polychlorinated and phenolic substances. In this study, we investigated human exposure to these chemicals over the past decade. Three hundred urine samples collected in 2009, 2013 and 2017 (100 samples each year) from young Danish men of the general population, participating in a large on-going cross-sectional study, were selected for the present time trend study. The urinary concentration of metabolites of 15 phthalates, di-2-ethylhexyl terephthalate (DEHTP) and di-iso-nonyl-cyclohexane-1,2-dicarboxylate (DINCH), seven bisphenols including BPA, bisphenol S (BPS) and bisphenol F (BPF), as well as triclosan, triclocarban, benzophenone-3, three chlorophenols and two phenylphenols were analyzed by two new sensitive LC-MS/MS methods developed and validated for the present study. A significant decrease in urinary concentrations over time was observed for the majority of the chemicals. Median concentrations of BPA and the metabolites of DiBP, DnBP, BBzP and DEHP were more than halved from 2009 to 2017. Similar decreases were observed for triclosan and the chloro- and phenylphenols. In contrast, metabolites of the two phthalate substitutes DEHTP and DINCH increased more than 20 and 2 times, respectively. The potential BPA substitutes; BPS and BPF also increased, but only slightly. Despite these new exposure patterns, the exposure to the old well-known chemicals, such as DiBP, DnBP, BBzP, DEHP and BPA was still higher in 2017 compared to the exposure level of the new substitutes such as DEHTP, DINCH, BPS and BPF. A significant decrease in internal exposure to most of the common phthalates and BPA over the past decade was observed, reflecting market changes and regulatory measures implemented in EU. Despite increasing exposures to some of the known phthalate substitutes and BPA analogues, the total amount of each measured chemical group (original and substitute analytes combined) was lower in the more recently collected samples. This indicates only partial direct substitution or substitution by chemicals not covered in this approach, or a general decline in the exposure to these chemical/product groups over the last decade.

Distinct urinary lipid profile in children with focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) accounts for the majority of new-onset end-stage renal disease (ESRD) during adolescence. FSGS treatment is a great challenge for pediatric nephrologists due to intertwined molecular pathways underlining its complex pathophysiology. There is emerging evidence showing that perturbed lipid metabolism plays a role in the pathophysiology of FSGS. We postulate that the nephrotic milieu in FSGS differs from minimal change disease (MCD) and that urinary lipidomics can be used as a tool for early diagnosis of FSGS. We explored the urinary lipid profile of patients with FSGS and MCD using an unbiased metabolomics approach. We discovered a unique lipid signature characterized by increased concentration of fatty acid (FA) and lysophosphatidylcholines (LPC) and a decrease in urinary concentration of phosphatidylcholine (PC) in patients with FSGS. These findings indicate increased metabolism of membrane phospholipid PC by phospholipase A2 (PLA2), resulting in higher urinary concentrations of LPC and FA. We propose that increased PC by-products can be used as a biomarker to diagnose FSGS and shed light on the mechanism of tubular and podocyte damage. Validation of identified urinary lipids as a biomarker in predicting the diagnosis and progression of FSGS in a larger patient population is warranted.

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

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.

818 THE IMPACT OF NON-UROLOGIC CONDITIONS ON QUALITY OF LIFE IN PATIENTS WITH INTERSTITIAL CYSTITIS

(110.6 106.2, p 0.05) and BDNF (650.4 474.2, p 0.05) and GDNF (811.7 728.8, p 0.05). At 3 and 6 months urinary neurotrophic factors increased up to similar levels to baseline. All BPS/IC patients improved significantly VAS (from 5.8 1.8 to 2.5 1.3), urinary frequency (from 16.2 3.7 to 9.7 31.8), OSS (from 29 6.4 to 18.1 3.6), and QoL (from 5.1 0.9 to 1.3 1.7). There was a positive correlation between the decrease in urinary concentration of NGF and BDNF and the decrease in VAS at 1-month follow-up, NGF (r2 0.53) and BDNF (r2 0.63). This positive correlation was also observed with OSS at same time period. CONCLUSIONS: When compared to controls, refractory BPS/IC patients exhibited urinary NGF and BDNF concentrations significantly higher than controls. As GDNF levels showed no differences, this observation implicates peptidergic bladder afferents in BPS/IC. NGF and BDNF decreased after OnabotA further confirming the positive effect of OnabotA in the disease.

Assessment of Urinary Concentrations of Hepcidin Provides Novel Insight into Disturbances in Iron Homeostasis during Malarial Infection

Disturbances in iron homeostasis are frequently observed in individuals with malaria. To study the effect of malaria and its treatment on iron homeostasis and to provide a mechanistic explanation for observed alterations in iron distribution, we studied the course of the iron regulatory hormone hepcidin in anemic Tanzanian children with febrile Plasmodium falciparum malaria. Before initiation of antimalarial treatment, urinary concentrations of hepcidin were strongly elevated and were associated with iron maldistribution, as was suggested by the presence of hypoferremia and high serum concentrations of ferritin. Antimalarial treatment resulted in a rapid decrease in urinary concentrations of hepcidin and reversal of the hypoferremia. Exploration of regulatory pathways of hepcidin production by analysis of iron, erythropoietic, and inflammatory indices suggested that reduced erythropoietic activity and inflammation stimulated hepcidin production. We conclude that high concentrations of hepcidin explain the observed disturbances in host iron homeostasis associated with malaria and may contribute to malarial anemia and an impaired erythropoietic response to iron supplementation.

Decreased Bone Resorption with Soy Isoflavone Supplementation in Postmenopausal Women

To investigate the effect of soy isoflavone supplementation on bone mineral density (BMD) and markers of bone turnover in postmenopausal women. In this randomized, placebo-controlled clinical trial, we used a crossover design to test the effect of soy isoflavone (110 mg/day) (1.3:1.0:0.22 ratio of genistein/daidzein/ glycitein) on bone formation, bone resorption, bone mineral content (BMC), and BMD for 6 months. Postmenopausal women (n = 19), mean age 70.6 +/- 6.3 years and mean time since menopause 19.1 +/- 5.5 years, were given isoflavone supplements for 6 months. There was a 37% decrease in urinary concentrations of type 1 collagen alpha1-chain helical peptide (HP), a marker of bone resorption, during the isoflavone supplementation compared with baseline (p < 0.05) and a significant difference in mean (SE) HP excretion levels when isoflavone was compared with placebo (43.4 +/- 5.2 vs. 56.3 +/- 7.2 microg/mmol creatinine [cr], p < 0.05). With isoflavone supplementation, mean spine BMD at L2 and L3 was significantly greater when treatment was compared with control, with a difference between means of 0.03 +/- 0.04 g and 0.03 +/- 0.04 g (p < 0.05), respectively. There were nonsignificant increases from baseline for total spine BMC (3.5%), total spine BMD (1%), total hip BMC (3.6%), and total hip BMD (1.3%) with the isoflavone treatment. Soy isoflavone, in isolated form, was effective in this study to significantly decrease bone resorption in postmenopausal women. Further investigation needs to be done to evaluate the long-term effects of soy isoflavone on bone mass and fracture risk.

DIE INAKTIVIERUNG VON INFUNDIERTEM VASOPRESSIN BEI DIABETES INSIPIDUS-PROBANDEN

ABSTRACT 30 experiments were performed in 6 human subjects with diabetes insipidus of the central type. The response of the target organ has been investigated after abrupt cessation of a several hours lasting vasopressin infusion of different dosage. Thereby only the decrease of the urinary osmolality followed about a simple exponential decline after a different time of latency. The mean values of vasopressin doses correlated with the urinary osmolalities at the end of the infusions, the latent periods and the »slopes of the osmolar decrease«. After an input rate of 6.7 ± 3.2 μU vasopressin/kg/min, the »half life of response« was 8.25 ± 2 min, and the latent period after the withdrawal of infusion until the beginning to decline amounted to 28.45 ± 8.5 min. The corresponding data of an infusion rate of 1.7 μU/kg/min were a »half life« period of 21.7 ± 6.15 min and a time of latency of 5.1 ± 3.2 min. The total time of decrease in urinary concentration, averaging 29 min, remained completely constant in all the tests, and it was not influenced by the hormonal dosis. Only in 16 experiments, however, the time of observation had been extended until the osmolality had diminished below 100 mOsm/kg. Here the duration of the decline lasted 32.1 min on average. Therefore it was supposed a real »time of detectable inactivation« of 32 to 35 min. From the obtained results a theory is discussed, concerning the quantitative relation between vasopressin and the receptor of the target organ, and the mode of inactivation occurring there.