sacubitril and Fibrosis

Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified.. Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2 μg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO + VAL (valsartan), and ALDO + SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid.. The ALDO + SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO + VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2, and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR.. In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability.

Topics: Aldosterone; Animals; Biphenyl Compounds; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fibrosis; Kidney; Male; Mice; Natriuretic Peptides; Renal Plasma Flow; Valsartan

Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS).. Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001).. Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.

Topics: Aminobutyrates; Animals; Apoptosis; Biphenyl Compounds; Cardio-Renal Syndrome; Cardiovascular Agents; Drug Combinations; Fibrosis; Humans; Inflammation; Kidney; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Simendan; Stroke Volume; Valsartan; Ventricular Function, Left

Female sexual dysfunction is common in hypertension. The effects of sacubitril/valsartan (SAC/VAL) as a potential therapy for hypertension and heart failure have not been studied in relation to sexual function and genital fibrosis in female spontaneously hypertensive rats (SHRs). Thirty female SHRs were administered VAL, SAC/VAL, or saline. Ten normotensive female Wistar-Kyoto (WKY) rats were included in the control group. We assessed estrous cyclicity and sexual behavior in the female rats. In addition, the morphology of clitoral and vaginal tissues was evaluated by histological analyses. Western blotting and enzyme-linked immunosorbent assays were used to assess the levels of fibrotic markers in vaginal and clitoral tissues. Furthermore, the protein levels of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), phosphoinositide-3-kinase (PI3K), and AKT expression were measured by Western blotting. SAC/VAL treatment improved hypertension-induced sexual dysfunction, exhibited as a prolonged estrus phase, increased receptivity and proceptive events, and decreased aggressive events, compared with those of VAL treatment and control SHRs without treatments. In addition, SAC/VAL-treated SHRs had lower levels of fibrotic markers, estradiol, and estrogen receptor α/β than the levels of VAL-treated SHRs or SHRs without treatment. Moreover, SAC/VAL decreased p-PTEN expression and increased p-PI3K and p-AKT expression at the protein level compared with those in VAL treatment alone. VAL and SAC/VAL treatments have significantly increased sexual receptivity and proceptivity, decreased aggressiveness, and improved the fibrosis of vaginal and clitoral tissues in female SHRs. However, SAC/VAL treatment shows more effective results compared with VAL treatment, which may be related to the PTEN/PI3K/AKT pathway.

Topics: Aminobutyrates; Animals; Biphenyl Compounds; Female; Fibrosis; Hypertension; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Valsartan

Sacubitril/Valsartan, a dual inhibitor of the neprilysin and angiotensin receptor, exerts cardioprotective effects in heart failure. Little is known on the impact of Sacubitril/Valsartan in hypertensive patients early post myocardial infarction.. Spontaneously hypertensive rats (SHR) were pretreated by daily angiotensin receptor blocker (ARB; 30 mg/kg intraperitoneally), Sacubitril/Valsartan (ARNI; 60 mg/kg intraperitoneally) or the same dosage of physiological saline for 1 week. Then each group underwent myocardial infarction induction and received the same treatment for another week. The blood pressure and cardiac function were evaluated prior to sacrifice. We performed histological and molecular evaluation of fibrosis in vivo and in vitro.. The blood pressure was comparable between three groups both 1 week prior to and post myocardial infarction. ARNI and ARB restore the decreased ejection fraction (57.3 ± 7.6 vs. 42.9 ± 5.2%, P < 0.05; 54.3 ± 6.9 vs. 42.9 ± 5.2%, P < 0.01, respectively) and fractional shortening (31.6 ± 5.4 vs. 22.1 ± 3.1%, P < 0.05; 29.4 ± 4.5 vs. 22.1 ± 3.1%, P < 0.05, respectively) post myocardial infarction. The infarct size and collagen deposition were also significantly mitigated in ARNI and ARB groups. In addition, ARNI and ARB treatment reduced the expression of cardiac remodeling-related factors, such as Bnp, α-SMA, Vimentin, and Col1a1 (all P < 0.05 vs. MI group). Finally, ARNI and ARB decreased the expression of α-SMA in cardiac fibroblasts treated with Ang II.. In conclusion, pretreatment with ARNI maintained cardiac function and reduced myocardial fibrosis in myocardial infarction, probably prior to any anti-hypertensive effect.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Drug Combinations; Fibrosis; Heart Failure; Hypertension; Myocardial Infarction; Rats; Rats, Inbred SHR; Tetrazoles; Valsartan

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Drug Combinations; Female; Fibrosis; Heart Failure; Rats; Rats, Inbred SHR; Stroke Volume; Tetrazoles; Valsartan

Sacubitril/valsartan (SAC/VAL) prevents angiotensin II (AngII) from binding AT1-R and blocks degradation of natriuretic peptides. Despite its efficacy in reducing ventricular fibrosis and preserving cardiac functions, which has been extensively demonstrated in myocardial infarction or pressure overload models, few studies have been conducted to determine whether SAC/VAL could attenuate atrial fibrosis and decrease atrial fibrillation (AF) susceptibility. Our study provided evidence for the inhibition of atrial fibrosis and reduced susceptibility to AF by SAC/VAL. After 28 days of AngII continuous subcutaneous stimulation, rats in SAC/VAL group exhibited reduced extent of atrial fibrosis, inhibited proliferation, migration, and differentiation of atrial fibroblasts, and decreased susceptibility to AF. We further found that inhibition of p-Smad2/3, p-JNK, and p-p38MAPK pathways is involved in the role of SAC/VAL on AngII-induced atrial fibrosis in vivo. These results emphasize the importance of SAC/VAL in the prevention of AngII-induced atrial fibrosis and may help to enrich the options for AF pharmacotherapy.

Topics: Aminobutyrates; Angiotensin II; Animals; Atrial Fibrillation; Biphenyl Compounds; Fibrosis; Rats; Signal Transduction; Valsartan