Browsing by Subject "Aldosterone"
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Item Aldosterone-induced proteins in primary cultures of rabbit renal cortical collecting system(1996-10) Bindels, Rend J.M.; Engbersen, A.M.T.; Hartog, A.; Blazer-Yost, BonniePrimary cultures of immunodissected cells from rabbit kidney connecting tubule and cortical collecting duct were used to study aldosterone's action on transcellular Na+ flux. Incubation with 10(-7) M aldosterone stimulated transcellular Na+ transport which was detected as an increase in benzamil-sensitive short-circuit current. The stimulatory response was consistently noted after 2 h of incubation and stabilized after 6 h. 2D-PAGE was used to identify proteins which were induced concurrently with the increase in transcellular Na+ flux after an aldosterone incubation of 15 h. Three aldosterone-induced proteins (AIPs; M(r) = 100, 70-77 and 46-50 kDa) were found in the membrane and microsomal fractions. Two of these appeared to have more than one isoform. A single heterogeneous AIP (M(r) = 77 kDa) was detected in the soluble fraction.Item Aldosterone-induced proteins in renal epithelia(1982-10-28) Blazer-Yost, Bonnie; Geheb, Michael A.; Preston, Alan; Handler, Joel; Cox, MalcolmSimilar aldosterone-induced proteins have been demonstrated in two renal epithelia, the urinary bladder of the toad, Bufo marinus, and epithelia formed by cells of the A6 line derived from the kidney of the toad, Xenopus laevis. The proteins are induced along with the stimulation of Na+ transport but their synthesis is not dependent on Na+ transport per se. In view of the similar characteristics of the aldosterone-induced proteins in these two different epithelia, we suggest that they may have an important role in aldosterone-induced Na+ transport.Item Association of Circulating Renin and Aldosterone With Osteocalcin and Bone Mineral Density in African Ancestry Families(American Heart Association, 2016-05) Kuipers, Allison L.; Kammerer, Candace M.; Pratt, J. Howard; Bunker, Clareann H.; Wheeler, Victor W.; Patrick, Alan L.; Zmuda, Joseph M.; Medicine, School of MedicineHypertension is associated with accelerated bone loss, and the renin-angiotensin-aldosterone system is a key regulator of blood pressure. Although components of this system are expressed in human bone cells, studies in humans are sparse. Thus, we studied the association of circulating renin and aldosterone with osteocalcin and bone mineral density. We recruited 373 African ancestry family members without regard to health status from 6 probands (mean family size: 62 and relative pairs: 1687). Participants underwent a clinical examination, dual-energy x-ray absorptiometry, and quantitative computed tomographic scans. Renin activity, aldosterone concentration, and osteocalcin were measured in fasting blood samples. Aldosterone/renin ratio was calculated as aldosterone concentration/renin activity. All models were analyzed using pedigree-based variance components methods. Full models included adjustment for age, sex, body composition, comorbidities, lifestyle factors, blood pressure, and antihypertensive medication. Higher renin activity was significantly associated with lower total osteocalcin and with higher trabecular bone mineral density (both P<0.01). There were also significant genetic correlations between renin activity and whole-body bone mineral density. There were no associations with aldosterone concentration in any model and results for aldosterone/renin ratio were similar to those for renin activity. This is the first study to report a significant association between renin activity and a marker of bone turnover and bone mineral density in generally healthy individuals. Also, there is evidence for significant genetic pleiotropy and, thus, there may be a shared biological mechanism underlying both the renin-angiotensin-aldosterone system and bone metabolism that is independent of hypertension.Item Dietary Electrolytes and their Influences on Plasma Aldosterone Concentration(2019-06) Ye, Xiaohan; Tu, Wanzhu; Katz, Barry P.; Bakoyannis, Giorgos; Yiannoutsos, Constantin T.Excessive sodium retention is thought to be the main culprit for hypertension. The modern American diet provides an excess of sodium and not sufficient amount of sodium. In this research, we examined the relations among urinary sodium and potassium excretion, and plasma levels of aldosterone, a mineralocorticoid hormone that has been linked to incidence hypertension, in a cohort of healthy children and young adults. We found that higher plasma aldosterone level was associated with lower sodium excretion in the urine, in blacks and whites, suggesting that aldosterone plays a critical role in retaining the sodium from dietary sources. The study highlights the importance of dietary sodium restriction.Item Finerenone in patients with chronic kidney disease and type 2 diabetes with and without heart failure: a prespecified subgroup analysis of the FIDELIO-DKD trial(Wiley, 2022) Filippatos, Gerasimos; Pitt, Bertram; Agarwal, Rajiv; Farmakis, Dimitrios; Ruilope, Luis M.; Rossing, Peter; Bauersachs, Johann; Mentz, Robert J.; Kolkhof, Peter; Scott, Charlie; Joseph, Amer; Bakris, George L.; Anker, Stefan D.; FIDELIO-DKD Investigators; Medicine, School of MedicineAims: This prespecified analysis of the FIDELIO-DKD trial compared the effects of finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, on cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) by history of heart failure (HF). Methods and results: Patients with T2D and CKD (urine albumin-to-creatinine ratio ≥30-5000 mg/g and estimated glomerular filtration rate [eGFR] ≥25-<75 ml/min/1.73 m2 ), without symptomatic HF with reduced ejection fraction (New York Heart Association II-IV) and treated with optimized renin-angiotensin system blockade were randomized to finerenone or placebo. The composite cardiovascular (CV) outcome (CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for HF) and composite kidney outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death) were analysed by investigator-reported medical history of HF. Of 5674 patients, 436 (7.7%) had a history of HF. Over a median follow-up of 2.6 years, the effect of finerenone compared with placebo on the composite CV outcome was consistent in patients with and without a history of HF (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06 and HR 0.90, 95% CI 0.77-1.04, respectively; interaction p = 0.33). The effect of finerenone on the composite kidney outcome did not differ by history of HF (HR 0.79, 95% CI 0.52-1.20 and HR 0.83, 95% CI 0.73-0.94, respectively; interaction p = 0.83). Conclusion: In FIDELIO-DKD, finerenone improved cardiorenal outcome in patients with CKD and T2D irrespective of baseline HF history.Item Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses From the FIGARO-DKD Trial(Wolters Kluwer, 2022) Filippatos, Gerasimos; Anker, Stefan D.; Agarwal, Rajiv; Ruilope, Luis M.; Rossing, Peter; Bakris, George L.; Tasto, Christoph; Joseph, Amer; Kolkhof, Peter; Lage, Andrea; Pitt, Bertram; FIGARO-DKD Investigators; Medicine, School of MedicineBackground: Chronic kidney disease and type 2 diabetes are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials, finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type 2 diabetes. These prespecified analyses from FIGARO-DKD assessed the effect of finerenone on clinically important HF outcomes. Methods: Patients with type 2 diabetes and albuminuric chronic kidney disease (urine albumin-to-creatinine ratio ≥30 to <300 mg/g and estimated glomerular filtration rate ≥25 to ≤90 mL per min per 1.73 m2, or urine albumin-to-creatinine ratio ≥300 to ≤5000 mg/g and estimated glomerular filtration rate ≥60 mL per min per 1.73 m2), without symptomatic HF with reduced ejection fraction, were randomized to finerenone or placebo. Time-to-first-event outcomes included new-onset HF (first hospitalization for HF [HHF] in patients without a history of HF at baseline); cardiovascular death or first HHF; HF-related death or first HHF; first HHF; cardiovascular death or total (first or recurrent) HHF; HF-related death or total HHF; and total HHF. Outcomes were evaluated in the overall population and in prespecified subgroups categorized by baseline HF history (as reported by the investigators). Results: Overall, 7352 patients were included in these analyses; 571 (7.8%) had a history of HF at baseline. New-onset HF was significantly reduced with finerenone versus placebo (1.9% versus 2.8%; hazard ratio [HR], 0.68 [95% CI, 0.50-0.93]; P=0.0162). In the overall population, the incidences of all HF outcomes analyzed were significantly lower with finerenone than placebo, including an 18% lower risk of cardiovascular death or first HHF (HR, 0.82 [95% CI, 0.70-0.95]; P=0.011), a 29% lower risk of first HHF (HR, 0.71 [95% CI, 0.56-0.90]; P=0.0043) and a 30% lower rate of total HHF (rate ratio, 0.70 [95% CI, 0.52-0.94]). The effects of finerenone on improving HF outcomes were not modified by a history of HF. The incidence of treatment-emergent adverse events was balanced between treatment groups. Conclusions: The results from these FIGARO-DKD analyses demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF.Item Hormonal regulation of the epithelial Na+ channel: From amphibians to mammals(2006-05) Shane, Michael Anne; Nofziger, Charity; Blazer-Yost, BonnieHigh-resistance epithelia derived from amphibian sources such as frog skin, toad urinary bladder, and the A6 Xenopus laevis kidney cell line have been widely used to elucidate the underlying mechanisms involved in the regulation of vectorial ion transport. More recently, the isolation of high-resistance mammalian cell lines has provided model systems in which to study differences and similarities between the regulation of ion transporter function in amphibian and mammalian renal epithelia. In the present study, we have compared the natriferic (Na+ retaining) responses to aldosterone, insulin, and vasotocin/vasopressin in the A6 and mpkCCDcl4 (mouse principal cells of the kidney cortical collecting duct) cell lines. The functional responses of the epithelial Na+ channel (ENaC) to hormonal stimulation were remarkably similar in both the amphibian and mammalian lines. In addition, insulin- and aldosterone-stimulated, reabsorptive Na+ transport in both cell lines requires the presence of functional PI3-kinase.Item Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in Kv channels(Springer, 2021-05-20) Goodwill, Adam G.; Baker, Hana E.; Dick, Gregory M.; McCallinhart, Patricia E.; Bailey, Chastidy A.; Brown, Scott M.; Man, Joshua J.; Tharp, Darla L.; Clark, Hannah E.; Blaettner, Bianca S.; Jaffe, Iris Z.; Bowles, Douglas K.; Trask, Aaron J.; Tune, Johnathan D.; Bender, Shawn B.; Anatomy, Cell Biology and Physiology, School of MedicineImpaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether MR blockade improves in vivo regulation of coronary flow, a process involving voltage-dependent K+ (Kv) channel activation, or reduces coronary structural remodeling in obesity is unclear. Thus, the goals of this investigation were to determine the effects of obesity on coronary responsiveness to reductions in arterial PO2 and potential involvement of Kv channels and whether the benefit of MR blockade involves improved coronary Kv function or altered passive structural properties of the coronary microcirculation. Hypoxemia increased coronary blood flow similarly in lean and obese swine; however, baseline coronary vascular resistance was significantly higher in obese swine. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, and did not restore coronary Kv function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening.Item Racial differences in sensitivity of blood pressure to aldosterone(Ovid Technologies Wolters Kluwer -American Heart Association, 2014-06) Tu, Wanzhu; Eckert, George J.; Hannon, Tamara S.; Liu, Hai; Pratt, Linda M.; Wagner, Mary Anne; Dimeglio, Linda A.; Jung, Jeesun; Pratt, J. Howard; Department of Medicine, IU School of MedicineBlacks in comparison with whites are at risk for a more serious form of hypertension with high rates of complications. Greater sodium retention is thought to underlie the blood pressure (BP)-determining physiology of blacks, but specific mechanisms have not been identified. In a prospective observational study of BP, 226 black children and 314 white children (mean age, 10.6 years) were enrolled initially. Assessments were repeated in 85 blacks and 136 whites after reaching adulthood (mean age, 31 years). The relationship of BP to plasma aldosterone concentration in the context of the prevailing level of plasma renin activity was studied in blacks and whites. In a secondary interventional study, 9-α fludrocortisone was administered for 2 weeks to healthy adult blacks and whites to simulate hyperaldosteronism. BP responses in the 2 race groups were then compared. Although black children had lower levels of plasma renin activity and plasma aldosterone, their BP was positively associated with the plasma aldosterone concentration, an effect that increased as plasma renin activity decreased (P=0.004). Data from black adults yielded similar results. No similar relationship was observed in whites. In the interventional study, 9-α fludrocortisone increased BP in blacks but not in whites. In conclusion, aldosterone sensitivity is a significant determinant of BP in young blacks. Although its role in establishing the risk of hypertension is not known, it could be as relevant as the actual level of aldosterone.Item Role of Adenosine A1 Receptors in Native Coronary Atherosclerosis, In-stent Stenosis, and Coronary Blood Flow Regulation in Metabolic Syndrome and Exercise(2010-04-08T13:47:08Z) Long, Xin; Sturek, Michael Stephen; Considine, Robert V.; Gunst, Susan J.; Herring, B. Paul; Tune, Johnathan D.Adenosine is widely thought to elicit coronary vasodilation and attenuate smooth muscle cell (SMC) proliferation, thereby providing cardioprotection. We cloned the porcine adenosine A1 receptor (A1R) subtype and found that it paradoxically stimulated proliferation of cultured coronary SMC by the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathways, thus suggesting A1R dysregulation could play a role in coronary artery disease (CAD), restenosis, and regulation of coronary blood flow (CBF). We utilized the Ossabaw swine model of metabolic syndrome (MetS) to test the hypothesis that A1R activation contributes to development of CAD, in-stent stenosis, and CBF regulation. Swine were fed standard chow (Lean) or excess calorie atherogenic diet for over 20 weeks, which elicited MetS characteristics and coronary atherosclerosis compared to Lean. We observed increased A1R in native CAD in MetS, which was reversed by exercise training, and upregulation of A1R expression and A1R-ERK1/2 activation in an in vitro organ culture model of CAD. Intracoronary stent deployment followed by different durations of recovery showed A1R upregulation occurred before maximal in-stent stenosis in vi vivo. More importantly, selective A1R antagonism with 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX)-eluting stents decreased coronary ERK1/2 activation and reduced in-stent stenosis comparable to Taxus® (paclitaxel-eluting stents). A1R antagonism potentiated vasodilatory effects of some vasodilators other than adenosine in porcine coronary microcirculation under basal conditions. Short-term exercise training around stenting prevented stent-induced microvascular dysfunction and attenuated native atheroma in the genetically lean Yucatan swine. Conclusions: A1R upregulation and activation contributes to coronary in-stent stenosis in vivo in MetS, plays a role in the development of coronary atherosclerosis in vitro, and might involve in CBF dysregulation in dyslipidemia and stenting. Exercise training decreased A1R expression in atherosclerosis, reduced native atheroma, and prevented stent-induced microvascular dysfunction. Selective pharmacological antagonism of A1R holds promise for treatment of CAD.