An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats.

Background: The aim of the study was to investigate the protective effect of canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism. Methods: High-salt diet was used to induce heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining, wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and protein expression analysis. Results: In this study, CANA showed diuretic, hypotensive, weight loss, and increased intake of food and water. Dahl salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed left ventricular remodeling and diastolic dysfunction caused by hypertension. After CANA treatment, cardiac hypertrophy and fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial glucose metabolism and increased fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-adenosine 5'-monophosphate-activated protein kinase (p-AMPK) and sirtuin 1 (SIRT1) and significantly induced the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a). Conclusion: CANA can improve myocardial hypertrophy, fibrosis, and left ventricular diastolic dysfunction induced by hypertension in DSS rats, possibly through the activation of the AMPK/SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.

Corticosteroids significantly increase cystatin C levels in the plasma by promoting cystatin C production in rats.

Background: Several studies have shown that non-renal factors such as corticosteroids may increase plasma cystatin C levels without affecting kidney function. However, the mechanisms underlying this are unclear. We hypothesized that corticosteroids may increase cystatin C levels in the plasma by promoting its production in tissues. In the present study, we aimed to test our hypothesis in rats by investigating the effect of corticosteroids on cystatin C production in tissues and the glomerular filtration rate (GFR), as measured by the gold standard method (i.e., inulin clearance). Results: Dexamethasone treatment was associated with much higher concentrations of cystatin C in all organ tissue homogenates tested. Dexamethasone increased plasma cystatin C levels in rats, without any decrease in renal inulin clearance. The impact of dexamethasone on plasma and organ tissue cystatin C levels was abolished by RU486, indicating the effect was glucocorticoid receptor-mediated. Conclusions: Our study provides direct evidence that corticosteroids may increase cystatin C levels in the plasma by promoting its production, without any decrease in GFR.

Corticosteroids Significantly Increase Serum Cystatin C Concentration without Affecting Renal Function in Symptomatic Heart Failure.

BACKGROUND: Human cystatin C is a single non-glycosylated polypeptide chain consisting of 120 amino acid residues. Its concentration in the circulation is mainly determined by glomerular filtration rate. However, non-renal factors, i.e., drugs, may dramatically affect its levels in the circulation. The aim of this study was to evaluate the effect of corticosteroid treatment on serum cystatin C concentration in patients with symptomatic heart failure. METHODS: Fifty-six symptomatic heart failure patients were treated with prednisone. Concentrations of serum cystatin C and serum creatinine were recorded at baseline, and after about 2 weeks of treatment. Twenty-four hour urinary creatinine was also measured to directly calculate glomerular filtration rate. RESULTS: Prednisone treatment significantly increased serum cystatin C concentration from 1.24 +/- 0.40 mg/L at baseline to 1.61 +/- 0.80 mg/L at the end of study (p < 0.05). However, the elevation in serum cystatin C concentration was not associated with renal function impairment. Prednisone not only significantly decreased serum creatinine concentrations from 89.66 +/- 28.63 pmol/L at baseline to 76.55 +/- 20.80 micromol/L after prednisone treatment (p < 0.05), but also significantly increased fractional excretion of sodium and urine flow rate. The data also showed there was a slight and but nonstatistically significant increase in glomerular filtration rate in such patients after prednisone treatment. CONCLUSIONS: Important non-renal factors, such as corticosteroids, can influence cystatin C concentration. Thus, it needs to be considered when interpreting cystatin C values in patients with heart failure receiving corticosteroid therapy.

Effect of Corticosteroid on Renal Water and Sodium Excretion in Symptomatic Heart Failure: Prednisone for Renal Function Improvement Evaluation Study.

BACKGROUND: Recent evidence indicates that prednisone can potentiate renal responsiveness to diuretics in heart failure (HF). However, the optimal dose of prednisone is not known. METHOD: Thirty-eight patients with symptomatic HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/d, n = 8), medium-dose (30 mg/d, n = 10), or high-dose prednisone (60 mg/d, n = 10), for 10 days. During this time, we recorded the 24-hour urinary output and the 24-hour urinary sodium excretion, at baseline, on day 5 and day 10. We also monitored the change in the concentration of serum creatinine, angiotensin II, aldosterone, high-sensitive C-reactive protein, tumor necrosis factor-α, interleukin 1ß, and interleukin 6. RESULTS: Low-dose prednisone significantly enhanced urine output. However, the effects of medium- and high-dose prednisone on urine output were less obvious. As for renal sodium excretion, high-dose prednisone induced a more potent natriuresis than low-dose prednisone. Despite the potent diuresis and natriuresis induced by prednisone, serum creatinine, angiotensin II, and aldosterone levels were not elevated. These favorable effects were not associated with an inflammatory suppression by glucocorticoids. CONCLUSIONS: Only low-dose prednisone significantly enhanced urine output. However, high-dose prednisone induced a more potent renal sodium excretion than low-dose prednisone.