Early short-term treatment with exogenous hydrogen sulfide postpones the transition from prehypertension to hypertension in spontaneously hypertensive rat

<p>Hydrogen sulfide (H₂S), nitric oxide (NO), and renin–angiotensin system (RAS) are involved in hypertension. We examined whether early treatment with sodium hydrosulfide (NaHS), an exogenous H₂S donor, can regulate H₂S-generating pathway, NO pathway, and the RAS, to prevent the transition from prehypertension to hypertension in spontaneously hypertensive rats (SHRs). Four-week-old SHRs and control normotensive Wistar–Kyoto (WKY) rats were assigned into three groups: WKY, SHRs, and SHR + NaHS; SHRs were injected intraperitoneally with sodium hydrosulfide (14 μmol/kg/day) for 4 weeks. SHRs exhibited hypertension at 12 weeks of age, which was blocked by early sodium hydrosulfide administration. Concentrations of H₂S were increased in the kidney in SHR + NaHS group versus WKY. Sodium hydrosulfide reduces mRNA expression of four H₂S-generating enzymes and decreased 3-mercaptopyruvate sulphurtransferase protein level in SHRs. Early administration of sodium hydrosulfide decreases plasma N^G monomethyl-l-arginine (l-NMMA, an inhibitor of NO synthase) level and increases plasma NO level in SHRs. Next, sodium hydrosulfide administration reduces renal mRNA expression of <i>Ren, Atp6ap2, Agt, Ace</i>, and <i>Agtr1a</i> in SHRs. We conclude that early short-term sodium hydrosulfide treatment increases renal H₂S concentrations, restores NO bioavailability, and blocks the RAS in the kidney, in favor of vasodilatation to prevent the development of hypertension in adult SHRs.</p

Table_1_Cardiovascular diseases morbidity and mortality among children, adolescents and young adults with dialysis therapy.DOCX

BackgroundThe age-specific burden of cardiovascular disease (CVD) and mortality in pediatric and young adult patients with end-stage kidney disease (ESKD) remains unclear. We aimed to examine the prevalence and incidence of CVD and all-cause mortality in children and adolescents compared with adults with dialysis in Taiwan.MethodsThis retrospective observational cohort study comprised 3,910 patients with more than 2 time point receipts of dialysis therapy in a year, including 156 aged ResultsAmong patients receiving dialysis treatment, the risk of composite CVD events [HR, 1.63 (1.22–2.19)] and mortality [HR, 1.76 (1.38–2.25)] was greater in children than the dialysis initiated in older patients. Non-atherosclerotic CVD was more prevalent, especially in younger patients, within the first 6 months after the initiation of dialysis. After 6 months of initial dialysis, the risk of atherosclerotic CVD was higher in adults than those for adolescents and children. The magnitude of CVD risk in adolescents who initiated dialysis therapy was higher in females [HR, 2.08 (1.50–2.88)] than in males [HR, 0.75 (0.52–1.10)].ConclusionYounger patients undergoing chronic dialysis with a higher risk of CVD events than older patients are associated with a faster onset of non-atherosclerotic CVD and a higher risk of both CVD- and non-CVD-related mortality.</p

The effects of PPADS intravenous injection on the response to acidic ATP solution in the bladder of controls and FFRs.

<p>Representative traces of bladder responses to acidic ATP solution instillation before and after intravenous PPADS administration in the control (A), FFRs with NDF (B), and FFRs with DO (C). (D): Purinergic antagonist effects of PPADS on the reduction of ICI during ATP solution stimulation among groups. An asterisk indicates a significant difference between before and after intravenous PPADS administration in the same group. (Paired t- test, p<0.05).</p

The effects of intravesical liposome administration on the response to acidic ATP solution stimulation in the bladder of controls and FFRs.

<p>Representative traces of bladder responses to acidic ATP solution instillation before and after intravesical liposome administration in the control (A), FFRs with NDF (B), and FFRs with DO (C). (D): Protective effects of liposomes on the reduction of ICI during ATP solution stimulation among groups. An asterisk indicates a significant difference between before and after intravesical liposome administration in the same group. (Paired t-test, p<0.05).</p

Alterations of receptor protein expression in the mucosa layer or smooth muscle layer of the bladder in controls and FFRs.

<p>Western blot analysis with specific antibodies to the TRPV1 receptor, purinergic P2X₂ receptor, and P2X₃ receptor of the rat mucosal layer and the purinergic P2X₁ receptor of the rat smooth muscle layer in controls and FFRs with different in cystometric presentations. A. TRPV1 receptor: The TRPV1 antibody produced a clear single band at 95kDa. B. Purinergic P2X₂ receptor C. Purinergic P2X₃ mature receptor: the predominant P2X₃ form (65kDa). D. Up-regulation of P2X3 native and intermediate polypeptides (up to 55kD) were shown in both FFR groups. E. Purinergic P2X₁ receptor Experiments were repeated two times and representative blots are shown. Data of proteins expression (ratios of signal intensities of investigated receptors relative to β-actin or GAPDH) were calculated with 8 samples in each group. These data of Mean ± SE were standardized and expressed in percentage in which the value of the control group is treated as 100%. Theses values were shown in the bar graph. An asterisk indicates a significant difference between controls and FFR groups (One-way ANOVA with Dunnett’s test, p<0.05).</p

Comparisons of general characteristics, biochemistry variables, and cystometric parameters among controls and FFRs.

<p>Data presented as mean ± SEM and tested among groups using one-way ANOVA with Dunnett’s test.</p>*<p>The Dunnett’s test showed a significant difference between the control group and other groups.</p>†<p>Homeostasis model assessment of insulin resistance (HOMA-IR) = fasting plasma insulin (µ U/ml)×fasting plasma glucose (mmol/l)/22.5.</p

Weights and renal outcome parameters in STZ-induced diabetic offspring at 12 weeks of age.

<p>STZ, offspring of STZ-induced diabetic mother; Cit, offspring of control mother treated with 0.25% l-citrulline; STZ+Cit, offspring of STZ-induced diabetic mother treated with 0.25% l-citrulline. KW, kidney weight; BW, body weight; BP, blood pressure; Cr, creatinine.</p>a<p>p<0.05 vs. control;</p>b<p>p<0.05 vs. STZ.</p

Alterations of renal arginine, ADMA, and arginine-to-ADMA ratio in the nSTZ offspring.

<p>Arginine, ADMA, and arginine-to-ADMA ratio in the kidneys of 1-week-old male offspring from nSTZ and control mothers. *p<0.05 vs. control.</p

Effect of ADMA on metanephros development.

<p>In vitro metanephros development in the (A) control, (B) 2 µM ADMA, or (C) 10 µM ADMA-supplemented medium. (D) The numbers of nephrons were counted. n = 6/group.</p

Protein levels of arginine-related enzymes in the STZ offspring kidney.

<p>(A) Representative western blots showing arginase II (Arg II, ∼40 kDa), cationic amino acid transporter-1 (CAT-1, ∼68 kDa), argininosuccinate synthase (ASS, ∼50 kDa), and argininosuccinate lysate (ASL, ∼50 kDa) bands. The relative abundances of renal cortical (B) arginase II, (C) CAT-1, (D) ASS, and (E) ASL were quantified. n = 6/group.</p