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Hypertension and proteinuria are important mediators of renal damage. Since H2S has vasodilatory, anti-inflammatory and antioxidant properties, we investigated its effects in Angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with H2S donors (NaHS or sodium thiosulfate (STS)) during three weeks of Ang II infusion reduced hypertension by 22% and 18% resp (p

Background Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic intervention, many renal patients ultimately progress to end stage renal disease. Hydrogen sulfide (H 2 S) is, in addition to nitric oxide and carbon monoxide, acknowledged as the third gasotransmitter sharing many physiological functions with these gases. It has vasodilatory, anti-inflammatory and anti-oxidant properties, making it an attractive candidate for pharmacological use in renal disease. We therefore investigated the protective properties of the H 2 S donor sodium hydrosulfide (NaHS) in Angiotensin II (AngII)-induced renal disease in rats. Methods Male Sprague Dawley rats were infused with AngII (435 ng/kg/min) or saline (control) for three weeks via subcutaneously placed osmotic minipumps. At placement of the pumps, rats were randomized to two different treatment regimens (vehicle and NaHS 5.6 mg/kg/day) and treated with intra-peritoneal injections twice a day during the three weeks of AngII infusion (n = 7/group). Control animals (n = 6) received vehicle injections only. Twenty-four hour urine was collected weekly. After three weeks, intra-aortic blood pressure was measured under anesthesia and subsequently rats were sacrificed. Upon sacrifice, plasma and kidneys were collected. Renal tissue was studied for tubular epithelial damage (Kidney Injury Molecule-1 (KIM-1)), interstitial fibrosis (collagen III), and upregulation of NADPH oxidase (NOX2). In an ex vivo experiment, rat kidneys (n = 4) in an isolated perfused kidney (IPK) setup were pre-contracted with phenylephrine (PE) (1uM) and subjected to 1 mM NaHS for 1 min. Before and after NaHS treatment intra-renal pressure was measured. Results Compared to controls, AngII infusion caused a 48% increase of systolic blood pressure (SBP) (142 vs 212 mmHg, p vs 346 mg/24 h, p vs 1.4 ml/min, p vs 212 mmHg, p vs 346 mg/24 h, p vs 1.4 ml/min, p Conclusion AngII induced hypertension, proteinuria and subsequent renal damage are markedly decreased by treatment with NaHS. Blood pressure regulation is a possible mechanism of renal tissue protection, but anti-proteinuric, anti-inflammatory and anti-oxidant effects may also play a role. Our data show that H 2 S might be a valuable addition to the already existing anti-hypertensive and reno-protective therapies.

Introduction Women who suffered from preeclampsia (PE) have an increased risk for cardiovascular and renal diseases later in life. Although the exact mechanisms underlying this relationship are unknown, they may relate to an increased sensitivity to angiotensin II (Ang-II) and endothelial dysfunction during a preeclamptic pregnancy, which may persist after PE. Recently, we showed vascular hypersensitivity to Ang-II and disturbed endothelial cell function in experimental PE in rats as compared to healthy pregnant rats. Objectives To study whether vascular hypersensitivity to Ang-II and endothelial dysfunction persist postpartum in experimental PE. Methods In this ongoing study, we thus far included non-pregnant rats (NP; n =9), formerly healthy pregnant rats (HP; n =9) and formerly experimental preeclamptic rats (PE; infusion of a low dose endotoxin; n =16). Six weeks after pregnancy, animals from each group were treated with Ang-II (osmotic minipump; 200ng/kg/min;NP: n =5;HP: n =6;PE: n =8) or were sham treated (NP: n =4;HP: n =3;PE: n =8). Blood pressure was measured in all rats one day before and weekly after Ang-II or sham treatment (for three weeks). At termination, the aortas of sham operated rats were obtained. Aortic rings (2mm) were mounted for isotonic measurement of vasotonus. Endothelium-dependent acetylcholine- (ACh) mediated vasodilation was studied in phenylephrine-preconstricted rings in the presence of vehicle, N G -nitro-L-arginine methyl ester, indomethacin or both, followed by full concentration response curves for ACh (10 −8 M–10 −4 M). Ang-II sensitivity was assessed by obtaining full concentration response curves (10 −10 M–10 −6 M). AT-1 and AT-2 receptor sensitivity was determined by administration of Ang-II in the presence of the AT-1 receptor blocker losartan, or the AT-2 receptor blocker PD123319. Results Our results indicate no difference in mean (±SD) systolic blood pressure (SBP) between the three groups six weeks after delivery (NP: 129(±7);HP: 127(±9);PE: 123(±10)mmHg; p =0.248). However, after three weeks of Ang-II treatment, a trend was found towards a stronger increase in SBP in PE rats as compared to HP rats (45.7(±18.9)% vs 63.4(±20.1)% respectively; p =0.081). Although we found no differences in in-vitro Ang-II sensitivity between the three groups, NP rats showed a trend towards an increased sensitivity of the AT-2 receptor to Ang-II compared to both groups of formerly pregnant rats. Total ACh-mediated endothelial relaxation was not different between the three groups. However, contribution of both NO and EDHF components to ACh-mediated relaxation seemed decreased in both groups of formerly pregnant rats as compared to the NP rats. Conclusion These preliminary data suggest that healthy rats that suffered from preeclampsia during pregnancy have increased in-vivo sensitivity to Ang-II postpartum as compared to rats with an uncomplicated pregnancy. Whether these differences are related to in-vitro- changes in Ang-II sensitivity or changes in endothelial function remains to be established.