Associations Between Aldosterone-Renin-Ratio and Bone Parameters Derived from Peripheral Quantitative Computed Tomography and Impact Microindentation in Men.

Components of the renin-angiotensin-aldosterone system (RAAS) are present on bone cells. One measure of RAAS activity, the aldosterone-renin-ratio (ARR), is used to screen for primary aldosteronism. Associations between ARR and bone mineral density are conflicting. This study investigated associations between ARR and peripheral quantitative computed tomography (pQCT) and impact microindentation (IMI). Male participants (n = 431) were from the Geelong Osteoporosis Study. "Likely" primary aldosteronism was defined as ARR ≥ 70 pmol/mIU. Another group, "possible" primary aldosteronism, was defined as either ARR ≥ 70 pmol/mIU or taking a medication that affects the RAAS, but not a beta blocker, and renin < 15 mU/L. Using pQCT, images at 4% and 66% of radial (n = 365) and tibial (n = 356) length were obtained. Using IMI measurements, bone material strength index (BMSi; n = 332) was determined. Associations between ARR or likely/possible primary aldosteronism and IMI or pQCT-derived bone parameters were tested using median regression. ARR and aldosterone values were not associated with any of the pQCT-derived bone variables in either unadjusted or adjusted analyses. Men with likely primary aldosteronism (n = 16), had lower adjusted total bone area (radial 66% site, - 12.5%). No associations were observed for men with possible primary aldosteronism (unadjusted or adjusted). No associations with BMSi were observed (p > 0.05). There were no associations between ARR or aldosterone and pQCT-derived bone parameters. Men with likely primary aldosteronism had lower bone area, suggesting clinically high levels of ARR may have a negative impact on bone health.

Fracture Risk and Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers.

Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9-79.1), range 50.0-96.6 yr; 574 women, median age 65.5 yr (58.1-75.4), range 50.1-94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2-13.2) and 10.9(6.3-11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00-2.37; 1.90, 1.18-3.05; 2.15, 1.26-3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34-5.29) and adjusted (2.03, 1.01-4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07-2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74-2.22). No other differences were observed. In men, lower dose (0 < DDD ≤ 1) ARB use was associated with an increased risk of fracture. ACEI or ARB use was not associated with increased risk of incident fracture in women. These findings may be important for antihypertensive treatment decisions in individuals with a high risk of fracture.

Association between bone measures and use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

Angiotensin-converting enzyme inhibitor use in women was associated with lower femoral neck and lumbar spine bone mineral density as well as trabecular bone score compared to non-users. No differences were identified for men or for those who used ARB medications. PURPOSE: Many individuals at high fracture risk use medications such as angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) that could affect bone; thus, this study aimed to investigate whether there are any differences in bone mineral density (BMD) and trabecular bone score (TBS) between ACEI users, ARB users, and non-users. METHODS: Participants (685 men, 573 women) were from the Geelong Osteoporosis Study. Current medication use was self-reported. BMD at the femoral neck (FNBMD) and lumbar spine (LSBMD) were measured using DXA. TBS was calculated using TBS iNsight software. Linear regression models were used to investigate associations between ACEI or ARB use and bone measures, adjusting for other potential confounders. Due to interaction terms, data were stratified by age. RESULTS: There were 88 (12.8%) men and 41 (7.2%) women taking an ACEI medication, and 71 (10.4%) men and 76 (13.3%) women taking an ARB medication. Compared to non-users, ACEI use was associated with lower FNBMD (- 7.2%), LSBMD (- 12.2%), and TBS (- 9.0%) for women aged < 65 years. Lower TBS was also observed for women aged ≥ 65 years (- 17.3%). No differences were identified for ARB use. CONCLUSIONS: Women who used an ACEI medication had lower values for FNBMD, LSBMD and TBS compared to non-users. No differences were identified for men or for those who used ARB medications.

Aldosterone deficiency in mice burdens respiration and accentuates diet-induced hyperinsulinemia and obesity.

Aldosterone synthase inhibitors (ASIs) should alleviate obesity-related cardiovascular and renal problems resulting partly from aldosterone excess, but their clinical use may have limitations. To improve knowledge for the use of ASIs, we investigated physiology in aldosterone synthase-knockout (ASKO) mice. On regular chow diet (CD), ASKO mice ate more and weighed less than WT mice, largely because they hyperventilated to eliminate acid as CO2. Replacing CD with high-fat diet (HFD) lessened the respiratory burden in ASKO mice, as did 12- to 15-hour fasting. The latter eliminated the genotype differences in respiratory workload and energy expenditure (EE). Thus, aldosterone deficiency burdened the organism more when the animals ate carbohydrate-rich chow than when they ate a HFD. Chronic HFD exposure further promoted hyperinsulinemia in ASKO mice that contributed to visceral fat accumulation accompanied by reduced lipolysis, thermogenic reprogramming, and the absence of weight-gain-related EE increases. Intracerebroventricular aldosterone supplementation in ASKO mice attenuated the HFD-induced hyperinsulinemia, but did not affect EE, suggesting that the presence of aldosterone increased the body's energetic efficiency, thus counteracting the EE-increasing effect of low insulin. ASIs may therefore cause acid-overload-induced respiratory burden and promote obesity. Their use in patients with preexisting renal and cardiopulmonary diseases might be contraindicated.

The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia.

BACKGROUND: In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome. METHODS: PCSK9 and plasma lipids were studied in nephrotic syndrome patients before and after remission of disease, mice with genetic ablation of the podocyte (Podocyte Apoptosis Through Targeted Activation of Caspase-8, Pod-ATTAC mice) and mice treated with nephrotoxic serum (NTS), which triggers immune-mediated podocyte damage. In addition, mice with hepatic deletion of Pcsk9 were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of nephrotic syndrome. RESULTS: Patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 on remission of their disease (P<0.05, n=47-50). Conversely, Pod-ATTAC mice and NTS-treated mice showed hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9. The induction of plasma PCSK9 appeared to be attributable to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the percentage of low-density lipoprotein-associated cholesterol (from 9% in vehicle-treated Flox mice to 47% after NTS treatment), was lost in mice with hepatic deletion of Pcsk9 (5% in both the presence and absence of NTS). CONCLUSIONS: Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia.

Immunity-Based Evolutionary Interpretation of Diet-Induced Thermogenesis.

Diet-induced thermogenesis (DIT) has often been argued to be a physiological defense against obesity, but no empirical proof of its effectiveness in limiting human body weight gain is available. We here propose an immune explanation of DIT-i.e., that it results from the coevolution of host and gut microbiota (especially Firmicutes) that ferment ingested food and proliferate, causing periodic, vagally mediated increases in thermogenesis aimed at curtailing their expansion. Because of this evolutionary adaptive significance related to the immune system, DIT is not effective as an "adaptation" to maintain a certain body mass. Were DIT an effective adaptation to prevent obesity, the current obesity epidemic might not have occurred.

Hsp90 blockers inhibit adipocyte differentiation and fat mass accumulation.

Geldanamycin derivatives are benzoquinone ansamycin antibiotics that bind to Hsp90 and alter its function. The alteration of Hsp90 activity limits some cellular hormonal responses by inhibiting nuclear receptors activation. The nuclear receptors activity, such as PPARγ, the mineralocorticoid and glucocorticoid receptors (MR and GR) play a critical role in the conversion of preadipocytes to mature adipocytes. Given the importance of these nuclear receptors for adipogenesis, we investigated the effects of geldanamycin analogues (GA) on adipocyte differentiation and function. We found that early exposure of preadipocyte cells to GA inhibited their conversion into mature adipocytes by inhibiting the adipogenic transcriptional program and lipid droplets accumulation. Furthermore, GA altered the adipokines secretion profile of mature adipocyte. The anti-adipogenic effect of GA was also confirmed in mice fed a high fat diet. Biochemical analysis revealed that anti-adipogenic effects of geldanamycin analogues may result from the simultaneous inhibition of MR, GR and PPARγ activity. Taken together, our observations lead us to propose Hsp90 as a potent target for drug development in the control of obesity and its related metabolic complications.