SIRT3 Activation by SGLT2 Inhibitor Mitigates Endothelial-to-Mesenchymal Transition in Dahl Salt-Sensitive Rats Induced by High-Salt Diet.

Objective To evaluate the risk of acute kidney injury (AKI) induced by sodium glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin). Methods Reports of AKI events induced by SGLT2 inhibitors and non-SGLT2 inhibitors received from January 1, 2013 to September 30, 2018 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database were collected. The relationship between the drugs mentioned above and the AKI events in all patients and especially in patients with diabetes mellitus, respectively, were analyzed by the method of reporting odds ratio (ROR). Results A total of 2 949 reports of SGLT2 inhibitors-induced AKI (2.50% of 117 843 AKI event reports in the database during the study period), and 114 894 reports of non-SGLT2 inhibitors-induced AKI were retrieved from the database. The ROR values of AKI events induced by overall SGLT2 inhibitors, canagliflozin, dapagliflozin, and empagliflozin in all patients were 4.14 (95%CI: 3.98-4.30), 5.58 (95%CI: 5.35-5.83), 2.62 (95%CI: 2.35-2.92), and 1.96 (95%CI: 1.76-2.19), respectively, and in patients with diabetes mellitus were 2.84 (95%CI: 2.71-2.98), 3.90 (95%CI: 3.69-4.12), 1.70 (95%CI: 1.48-1.94), and 1.30 (95%CI: 1.15-1.48), respectively. Due to the short time to market, less than 3 reports of AKI events induced by ertugliflozin were reported, thus ROR analysis was not conducted for ertugliflozin. The analyses of combined medication showed that in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 8.05 (95%CI: 7.10-9.13) when SGLT2 inhibitors were combined with diuretics, which increased by 80.90% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 6.07 (95%CI: 5.27-7.00), which increased by 92.09%; in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 5.87 (95%CI: 4.89-7.04) when SGLT2 inhibitors were combined with non-steroidal anti-inflammatory drugs (NSAID), which increased by 39.43% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 4.66 (95%CI: 3.79-5.74), which increased by 61.25%; in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 5.60 (95%CI: 5.12-6.14) when SGLT2 inhibitors were combined with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which increased by 25.56% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 4.05 (95%CI: 3.66-4.48), which increased by 27.36%. Conclusions SGLT2 inhibitors might increase the risk of AKI and this risk was mainly from canagliflozin, suggesting that dapagliflozin and empagliflozin were relatively safe to patients. The risk of AKI might increase when SGLT2 inhibitors were combined with diuretics or NSAID. Key words: Sodium-glucose transporter 2 inhibitors; Diabetes mellitus; Acute kidney injury; Odds ratio; Drug interaction; Adverse drug reaction reporting systems

Both diabetic and hypertensive nephropathy eventually progress to glomerulosclerosis. Previous studies revealed a potential role of endothelial-to-mesenchymal transition (EndMT) in the pathophysiology of glomerulosclerosis in diabetic rats. Therefore, we hypothesized that EndMT was also involved in the development of glomerulosclerosis in salt-sensitive hypertension. We aimed to explore the effects of high-salt diet on endothelial-to-mesenchymal transition (EndMT) in glomerulosclerosis in Dahl salt-sensitive (Dahl-SS) rats. Eight-week-old male rats were fed high-salt (8%NaCl; DSH group) or normal salt (0.3%NaCl; DSN group) for eight weeks, with systolic blood pressure (SBP), serum creatinine, urea, 24-hour urinary protein/sodium, renal interlobar artery blood flow, and pathological examination measured. We also examined endothelial-(CD31) and fibrosis-related protein(α-SMA) expressions in glomeruli. High-salt diet increased SBP (DSH vs. DSN, 205.2 ± 8.9 vs. 135.4 ± 7.9 mm Hg, P < 0.01), 24-hour urinary protein (132.55 ± 11.75 vs. 23.52 ± 5.94 mg/day, P < 0.05), urine sodium excretions (14.09 ± 1.49 vs. 0.47 ± 0.06 mmol/day, P < 0.05), and renal interlobar artery resistance. Glomerulosclerosis increased (26.1 ± 4.6 vs. 7.3 ± 1.6%, P < 0.05), glomerular CD31 expressions decreased while α-SMA expression increased in DSH group. Immunofluorescence staining showed that CD31 and α-SMA co-expressed in glomeruli of the DSH group. The degree of glomerulosclerosis negatively correlated with CD31 expressions (r = -0.823, P < 0.01) but positively correlated with α-SMA expressions (r = 0.936, P < 0.01). We demonstrated that a high-salt diet led to glomerulosclerosis involving the EndMT process, which played an essential role in glomerulosclerosis in hypertensive Dahl-SS rats.

To study the promotive effect of salt-induced hypertension on crystal deposition and urolithiasis using a salt-sensitive rat hypertension model. Hyperoxaluria and hypercalciuria were induced in male Dahl salt-sensitive rats with administration of ethylene glycol and alfacalcidol. Hypertension was induced by a high-salt diet. Eplerenone, a selective mineralocorticoid receptor antagonist, was given. Blood and urine were collected to evaluate renal function, electrolytes and the blood renin-angiotensin-aldosterone system. Renal calcium content was also evaluated. Histological examination, transcriptome analysis with DNA microarray and semiquantitative reverse transcriptase polymerase chain reaction were carried out. A high-salt diet increased crystal deposition in Dahl salt-sensitive rats with hypertension, and eplerenone administration significantly suppressed it. The mRNA expression profile was associated with crystal formation, growth, adhesion and cellular injury, and it was regulated in the group exposed to a high-salt diet and ethylene glycol. A high-salt diet has a promotive effect on salt-sensitive hypertension and urolithiasis. This promotive effect can be prevented by eplerenone administration. Hence, salt-sensitive hypertension has promotive effects on crystal deposition in Dahl salt-sensitive rats.

Effects of a high-salt diet on adipocyte glucocorticoid receptor and 11-β hydroxysteroid dehydrogenase 1 in salt-sensitive hypertensive rats

Evidence indicates the immune system is important in development of hypertension and kidney disease. In the Dahl Salt‐Sensitive (SS) rat model, lymphocytes play a role in development of hypertension and kidney damage after increased sodium intake. Recent transcriptomic analyses demonstrate upregulation of the innate immune complement system in the kidney of Dahl SS rat fed a high‐salt diet, leading us to hypothesize that inhibition of complement activation would attenuate development of hypertension and kidney damage. Male Dahl SS rats on a low salt (0.4% NaCl) diet were instrumented with telemeters for continuous monitoring of arterial blood pressure. Animals received saline vehicle (Control) or sCR1, a soluble form of endogenous Complement Receptor 1 (CR1; CD35) that inhibits complement activation. At Day 0, rats were switched to high salt (4.0% NaCl) diet and assigned to sCR1 (15 mg/kg per day) or Control groups with daily ip injections either days 1–7 or days 14–18. Urine was collected overnight for determination of albumin excretion. Treatment with sCR1, either immediately after high‐salt diet was initiated, or at days 14–18, did not alter development of hypertension or albuminuria. The sCR1 dose effectively inhibited total hemolytic complement activity as well as C3a generation. High salt caused an increase in message for complement regulator Cd59, with minimal change in Crry that controls the C3 convertase. Thus, innate immune complement activation in the circulation is not critical for development of hypertension and kidney damage due to increased sodium intake, and therapeutic manipulation of the complement system is not indicated in salt‐sensitive hypertension.

Exercise training has antihypertensive and renoprotective effects in humans and rats. However, the effects of exercise training on renal disorders that occur with salt-sensitive hypertension remains unclear. The study aim was to investigate the effects and mechanisms of exercise training on renal function in a rat model of salt-sensitive hypertension. Six-week-old male Dahl salt-sensitive rats were divided into normal-salt (0.6% NaCl) diet, high-salt (8% NaCl) diet, and high-salt diet with exercise training groups. The high-salt diet with exercise training group underwent daily treadmill running for 8 weeks. The high-salt diet induced severe hypertension and renal dysfunction. Exercise training significantly improved high-salt diet-induced urinary protein, albumin, and L-type fatty acid-binding protein excretion, and glomerulosclerosis but not renal interstitial fibrosis without changing blood pressure. Exercise training significantly attenuated high-salt diet-induced oxidative stress in the kidneys and decreased high-salt diet-stimulated xanthine oxidoreductase activity but not nicotinamide adenine dinucleotide phosphate oxidase activity. The high-salt diet did not change urinary excretion of 20-hydroxyeicosatetraenoic acid and decreased cytochrome P450 4A protein expression in the kidneys. Exercise training increased urinary 20-hydoroxyeicosatetraenoic acid excretion and renal cytochrome P450 4A protein expression. Exercise training improved renal disorders without lowering blood pressure in Dahl salt-sensitive rats. Exercise training also decreased oxidative stress and increased 20-hydroxyeicosatetraenoic acid production in the kidneys. These results suggest that improvements in oxidative stress and 20-hydroxyeicosatetraenoic acid production may be potential mechanisms by which exercise training improved renal disorders in Dahl salt-sensitive rats.

Objective: The epithelial sodium channel (ENaC) in the kidney plays pivotal roles in blood pressure regulation, and the γ subunit is activated by extracellular serine proteases. In proteinuric renal diseases, plasmin filtered through injured glomeruli proteolytically activates γENaC. In addition, filtered plasmin directly causes podocyte injury. We previously reported that Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet developed severe hypertension and proteinuria together with γENaC activation, and that a synthetic serine protease inhibitor, camostat mesilate, mitigated these changes. However, the role of plasmin in DS rats remains unclear. In this study, we evaluated the relationship between plasmin and hypertension as well as glomerular injury and the effects of plasmin inhibitors in DS rats. Design and method: Five-week-old male DS rats were divided into normal-salt (NS) diet, HS diet, and HS + plasmin inhibitors [tranexamic acid (TA, 2 mg/mL TA in drinking water) and synthetic plasmin inhibitor YO-2 (4 mg/kg/day, intraperitoneal injection)] groups. After systolic blood pressure measurement and 24-h urine collection over time for 5 weeks, the rats were sacrificed for biochemical examination. Results: The HS group displayed severe hypertension and proteinuria together with activation of plasmin in urine and γENaC in the kidney, which were not attenuated by TA. On the other hand, YO-2 mitigated both hypertension and proteinuria [SBP (mmHg): NS, 130.8 ± 7.5; HS, 209.0 ± 14.2; HS+YO-2, 183.8 ± 8.4; Urinary protein (mg/day): NS, 15.4 ± 3.2; HS 259.0 ± 129.3; HS+YO-2, 94.5 ± 31.5]. YO-2 inhibited the attachment of plasmin(ogen) to podocytes and alleviated podocyte injury by reducing glomerular apoptotic cells. Furthermore, YO-2 suppressed the upregulation of protease-activated receptor-1 and phosphorylated ERK1/2 as well as mRNA expression of inflammatory and pro-fibrotic cytokines in the kidney. Conclusion: These results indicate that plasmin plays important roles in the development of salt-sensitive hypertension and glomerular injuries in a rat model of hypertension, and suggest that plasmin inhibition could be a potential therapeutic strategy against salt-sensitive hypertension.

Although relaxin (RLX) has potent vasodilatory and anti-fibrotic properties, there is no information on its effects on salt-sensitive hypertension. We investigated the effects of short-term treatment with RLX on blood pressure (BP) and nitric oxide synthase (NOS) protein in the kidneys of male Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats after 1 week consumption of an 8% NaCl diet. We also evaluated the inhibitory effects of each specific NOS inhibitor on BP during 1-week RLX treatment under high-salt diet. Next, we examined the long-term effects of RLX treatment for 6 weeks on renal histology and transforming growth factor-beta1 (TGF-β1) expression in male DS and DR rats placed on the 8-week high-salt diet. The short-term RLX treatment significantly attenuated the high-salt diet-induced rise in BP in DS rats with increasing neuronal NOS and endothelial NOS protein in kidneys. Selective inhibition of each of the three NOS isoforms significantly blocked the anti-hypertensive effects of RLX in DS rats after 1-week high-salt diet. The long-term treatment of DS rats with RLX for 6 weeks significantly reduced systolic BP, lessened glomerular and tubulointerstitial changes and reduced TGF-β signaling compared to saline-treated controls. The results suggested that RLX converted salt sensitivity to salt resistance, at least in part, by up-regulating NOS. RLX is a potentially useful therapeutic agent for salt-sensitive hypertension.

Hypertension is a risk factor for atrial fibrillation (AF), and brain and muscle arnt-like protein 1 (Bmal1) regulate circadian blood pressure and is implicated in several fibrotic disorders. Our hypothesis that Bmal1 inhibits atrial fibrosis and susceptibility to AF in salt-sensitive hypertension (SSHT) and our study provides a new target for the pathogenesis of AF induced by hypertension. The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). An experimental model was used to measure systolic blood pressure (SBP), left atrial ejection fraction (LAEF), left atrial end-volume index (LAEVI), left atrial index (LAFI), AF inducibility, AF duration, and atrial fibrosis pathological examination and the expression of Baml1 and fibrosis-related proteins (TNF-α and α-SMA) in left atrial tissue. DSH increased TNF-α and α-SMA expression in atrial tissue, level of SBP and LAESVI, atrial fibrosis, AF induction rate, and AF duration, and decreased Bmal1 expression in atrial tissue, the circadian rhythm of hypertension, and level of LAEF and LAFI. Our results also showed that the degree of atrial fibrosis was negatively correlated with Bmal1 expression, but positively correlated with the expression of TNF-α and α-SMA. We demonstrated that a high-salt diet leads to circadian changes in hypertension due to a reduction of Bmal1 expression, which plays a crucial role in atrial fibrosis and increased susceptibility to AF in SSHT rats.

Accumulating evidence indicates that inflammation is implicated in hypertension. However, the role of brain proinflammatory cytokines (PICs) in salt sensitive hypertension remains to be determined. Thus, the objective of this study was to test the hypothesis that high salt (HS) diet increases PICs expression in the paraventricular nucleus (PVN) and leads to PVN neuronal activation. Eight-week-old male Dahl salt sensitive (Dahl S) rats, and age and sex matched normal Sprague Dawley (SD) rats were divided into two groups and fed with either a HS (4% NaCl) or normal salt (NS, 0.4% NaCl) diet for 5 consecutive weeks. HS diet induced hypertension and significantly increased cerebrospinal fluid (CSF) sodium concentration ([Na+]) in Dahl S rats, but not in normal SD rats. In addition, HS diet intake triggered increases in mRNA levels and immunoreactivities of PVN PICs including TNF-α, IL-6, and IL-1β, as well as Fra1, a chronic marker of neuronal activation, in Dahl S rats, but not in SD rats. Next, we investigated whether this increase in the expression of PVN PICs and Fra1 was induced by increased CSF [Na+]. Adult male SD rats were intracerebroventricular (ICV) infused with 8 μl of either hypertonic salt (4 μmol NaCl), mannitol (8 μmol, as osmolarity control), or isotonic salt (0.9% NaCl as vehicle control). Three hours following the ICV infusion, rats were euthanized and their PVN PICs expression was measured. The results showed that central administration of hypertonic saline in SD rats significantly increased the expression of PICs including TNF-α, IL-6, and IL-1β, as well as neuronal activation marker Fra1, compared to isotonic NaCl controls and osmolarity controls. Finally, we tested whether the increase in PICs expression occurred in neurons. Incubation of hypothalamic neurons with 10 mM NaCl in a culture medium for 6 h elicited significant increases in TNF-α, IL-6, and Fra1 mRNA levels. These observations, coupled with the important role of PICs in modulating neuronal activity and stimulating vasopressin release, suggest that HS intake induces an inflammatory state in the PVN, which, may in turn, augments sympathetic nerve activity and vasopressin secretion, contributing to the development of salt sensitive hypertension.

The aims of the present study were to determine the mechanism underlying enhanced neuronal nitric oxide synthase (nNOS) activity in the brain of hypertensive Dahl salt-sensitive (DSS) rats and the consequences of enhanced nNOS activity. Male DSS rats were fed either a regular (0.4% NaCl) or high-salt (8% NaCl) diet, with or without 0.25% nifedipine, for 4 weeks. The effects of nifedipine, which lowers blood pressure peripherally, on central nNOS were determined by measuring nNOS activity, as well as the number of nNOS-positive neurons in the brain stem and diencephalon. The effects of chronic (12 days) infusion of 7 μg (0.5 μL/h, i.c.v.) S-methyl-L-thiocitrulline (SMTC; a stereoselective competitive nNOS inhibitor) on mean arterial pressure were assessed in conscious DSS rats using a radiotelemetry system. In addition, the number of central nNOS-positive neurons was compared between DSS and salt-insensitive Sprague-Dawley rats. Normalization of blood pressure by nifedipine attenuated the increase in nNOS activity in the brain stem of DSS rats. Chronic i.c.v. infusion of SMTC further enhanced hypertension in DSS rats. Feeding of a high-salt diet increased nNOS-positive neurons in the lateral parabrachial nucleus, rostral ventrolateral medulla and nucleus tractus solitarius of DSS compared with Sprague-Dawley rats, whereas nNOS-positive neurons in the paraventricular nucleus remained downregulated in DSS rats. The results of the present study suggest that hypertension, rather than a high-salt diet, increases central nNOS activity in hypertensive DSS rats to buffer high blood pressure. However, this compensatory response may be insufficient to relieve salt-induced hypertension.

Background In phase III SOLAR-1 trial (NCT02437318), the PI3K alpha selective inhibitor alpelisib (ALP) + fulvestrant significantly improved progression-free survival vs. fulvestrant alone in patients with HR+/HER2- advanced breast cancer with PIK3CA mutations. Hyperglycemia is an on-target adverse effect of ALP that led to 6% of patient discontinuation in the ALP arm. Recently, Sodium-glucose co-transporter 2 (SGLT2) inhibition was reported to reduce PI3K inhibition-induced glucose and insulin increase. For 6 SOLAR-1 patients, the addition of an SGLT2 inhibitor to metformin (MET) and ALP stabilized blood glucose levels, allowing them to continue ALP treatment. Methods Brown Norway (BN) rat and Rat1-myr-p110α tumor bearing nude rat in vivo models were used to further investigate the degree of glucose and insulin control achievable upon treatment with ALP and a SGLT2 inhibitor dapagliflozin (DAPA) +/- MET and effects on ALP tolerability and efficacy. Results In both rat models tested, the addition of DAPA to ALP nearly suppressed ALP-induced hyperglycemia, was associated with insulin level reduction and insulin sensitivity improvement and no signs for ketoacidosis upon single agent (S.A) nor combination were observed under fed conditions. ALP S.A efficacy in the Rat1-myr-p110α tumor bearing nude rats was maintained when used in combination with DAPA and there was no influence of DAPA on ALP-induced body weight loss (BWL). In BN rats, when combining MET with ALP, a delay in blood glucose reduction was observed vs. DAPA + ALP combination. The triple combination of MET + DAPA + ALP improved further blood glucose levels reduction with the same kinetic as DAPA + ALP. MET + DAPA + ALP triple combination was more effective in reducing plasma insulin levels when compared to MET + ALP or DAPA + ALP double combinations. All combinations tested with MET slightly increased BYL719-induced BWL in BN rats. Conclusions SGLT2 inhibitors such as DAPA significantly reduced hyperglycemia and improved hyperinsulinemia induced by ALP in rat models without further BWL induced by ALP. These results warrant further clinical investigation of adding SGLT2 inhibitors +/- metformin to treat ALP-induced hyperglycemia. Citation Format: Christian R. Schnell, Daniel Wyss, Walter Tinetto, Thomas Ferrat, Jiaping Gao, Panza Darrell, Josh Gold, Valerie Beaulieu, John Diener, Christine Fritsch. SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P137.

Diabetic cardiomyopathy (DCM) is one of the leading causes of heart failure in patients with diabetes mellitus, with limited effective treatments. The cardioprotective effects of sodium‐glucose cotransporter 2(SGLT2) inhibitors have been supported by amounts of clinical trials, which largely fills the gap. However, the underlying mechanism still needs to be further explored, especially in terms of its protection against cardiac fibrosis, a crucial pathophysiological process during the development of DCM. Besides, endothelial‐to‐mesenchymal transition (EndMT) has been reported to play a pivotal role in fibroblast multiplication and cardiac fibrosis. This study aimed to evaluate the effect of SGLT2 inhibitor dapagliflozin (DAPA) on DCM especially for cardiac fibrosis and explore the underlying mechanism. In vivo, the model of type 2 diabetic rats was built with high‐fat feeding and streptozotocin injection. Untreated diabetic rats showed cardiac dysfunction, increased myocardial fibrosis and EndMT, which was attenuated after treatment with DAPA and metformin. In vitro, HUVECs and primary cardiac fibroblasts were treated with DAPA and exposed to high glucose (HG). HG‐induced EndMT in HUVECs and collagen secretion of fibroblasts were markedly inhibited by DAPA. Up‐regulation of TGF‐β/Smad signalling and activity inhibition of AMPKα were also reversed by DAPA treatment. Then, AMPKα siRNA and compound C abrogated the anti‐EndMT effects of DAPA in HUVECs. From above all, our study implied that DAPA can protect against DCM and myocardial fibrosis through suppressing fibroblast activation and EndMT via AMPKα‐mediated inhibition of TGF‐β/Smad signalling.

MP4-04 URINE STORAGE DYSFUNCTION IN RATS WITH SALT-LOADING HYPERTENSION DEPENDS ON INCREASE IN ATP AND PGE2 RELEASE FROM THE UROTHELIUM

HomeCirculationVol. 118, No. suppl_18Abstract 1486: Activated Vitamin D Regresses Cardiac Hypertrophy and Attenuates Progression to Heart Failure in Dahl Salt-Sensitive Rats Free AccessMeeting ReportAboutSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessMeeting ReportBasic ScienceCardiorenal Physiology/PathophysiologyAbstract 1486: Activated Vitamin D Regresses Cardiac Hypertrophy and Attenuates Progression to Heart Failure in Dahl Salt-Sensitive Rats Bhargavi Yalamarti, Qingen Ke, Natalya Bodyak, Isaac Stillman, Hector Tamez, S. A Karumanchi, Ravi Thadhani and Peter M Kang Bhargavi YalamartiBhargavi Yalamarti Search for more papers by this author , Qingen KeQingen Ke Search for more papers by this author , Natalya BodyakNatalya Bodyak Search for more papers by this author , Isaac StillmanIsaac Stillman Search for more papers by this author , Hector TamezHector Tamez Search for more papers by this author , S. A KarumanchiS. A Karumanchi Search for more papers by this author , Ravi ThadhaniRavi Thadhani Search for more papers by this author and Peter M KangPeter M Kang Search for more papers by this author Originally published28 Oct 2008https://doi.org/10.1161/circ.118.suppl_18.S_335-aCirculation. 2008;118:S_335AbstractVitamin D deficiency is a common but often unrecognized condition in patients with heart failure. We previously demonstrated that activated vitamin D (AVD) therapy prevents the progression of cardiac hypertrophy in Dahl salt sensitive (DSS) rats on a high salt (HS) diet ( PNAS2007; 104 :16810Google Scholar). Here we asked whether AVD can cause pre-existing cardiac hypertrophy to regress and/or attenuate the progression of heart failure.Methods: To generate cardiac hypertrophy, male DSS rats were fed a HS diet (6% NaCl) from 6 to 11 weeks of age. All animals develop compensated cardiac hypertrophy at 11 weeks, and baseline measurements were obtained (HS-C). The remaining animals divided into three groups:HS diet with vehicle injection x 4 weeks (HS+V)HS diet with paricalcitol (PC, 200ng IP 3x/wk) injection x 4 weeks (HS+PC)normal diet (ND). They were evaluated at 15 weeks.Results: Compared to hypertrophic baseline (HS-C), the HS+PC group showed a significant reduction in heart weight/tibial length (TL) ratio after 4 weeks (−10 %, p<0.05), whereas the HS+V and ND groups did not (both +2%, p=NS). There were similar reductions compared with baseline in septal and posterior wall thicknesses on echocardiograms (HS+PC: −18% and −20%, respectively, vs. 0% and 0% in HS+V, p<0.05). We also found a significant increase in the lung weight/TL ratio indicative of progressing heart failure in the HS+V group compared with baseline (+73%, p<0.05), which was reduced either by PC treatment or by changing to ND (−18% and −53%, p<0.05 for both). The attenuation of heart failure was also indicated by reductions in LV mass (−7% vs. +20%, p<0.05) and reduced fractional shortening (FS) (−15% vs. −35%, p<0.05) in PC compared to HS+V. Switching to ND, however, resulted in the attenuation of FS only (−11%, p<0.05). We also found a reduction of plasma BNP levels in HS+PC and ND compared to HS+V treated animals (−50% and −59%, P<0.05 for both), and, finally, significantly lower cardiomyocyte hypertrophy and intra-cardiac arteriolar diameter in HS+PC vs. HS+V treated animals.Conclusion: PC treatment resulted in the regression of pre-existing cardiac hypertrophy in DSS animals. Both PC treatment and a change to a normal diet attenuated the progression of clinical and biochemical signs of heart failure. Previous Back to top Next FiguresReferencesRelatedDetails October 28, 2008Vol 118, Issue suppl_18 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.118.suppl_18.S_335-a Originally publishedOctober 28, 2008 Advertisement