Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia.

Preeclampsia (PE) is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy and is associated with oxidative stress and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs). Inhibition of the AT1-AAs in the reduced uterine perfusion pressure (RUPP) rat, a model of PE, attenuates hypertension and many other characteristics of PE. We have previously shown that mitochondrial oxidative stress (mtROS) is a newly described PE characteristic exhibited by the RUPP rat that contributes to hypertension. However, the factors that cause mtROS in PE or RUPP are unknown. Thus, the objective of the current study is to use pharmacologic inhibition of AT1-AAs to examine their role in mtROS in the RUPP rat model of PE. AT1-AA inhibition in RUPP rats was achieved by administration of an epitope-binding peptide ('n7AAc'). Female Sprague-Dawley rats were divided into the following two groups: RUPP and RUPP + AT1-AA inhibition (RUPP + 'n7AAc'). On day 14 of gestation (GD), RUPP surgery was performed; 'n7AAc' peptide (2 µg/µL) was administered by miniosmotic pumps in a subset of RUPP rats; and on GD19, sera, placentas, and kidneys were collected. mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. Placental and renal mitochondrial respiration and mtROS were improved in RUPP + 'n7AAc' rats compared with RUPP controls. Moreover, endothelial cells (human umbilical vein endothelial cells) treated with RUPP + 'n7AAc' sera exhibited less mtROS compared with those treated with RUPP sera. Overall, our findings suggest that AT1-AA signaling is one stimulus of mtROS during PE.

Low-dose testosterone protects against renal ischemia-reperfusion injury by increasing renal IL-10-to-TNF-α ratio and attenuating T-cell infiltration.

Renal ischemia-reperfusion (I/R) in male rats causes reductions in plasma testosterone, and infusion of testosterone 3 h postreperfusion is protective. We tested the hypotheses that acute high doses of testosterone promote renal injury after I/R, and that acute low-dose testosterone is protective by the following: 1) increasing renal IL-10 and reducing TNF-α; 2) its effects on nitric oxide; and 3) reducing intrarenal T-cell infiltration. Rats were subjected to renal I/R, followed by intravenous infusion of vehicle or testosterone (20, 50, or 100 µg/kg) 3 h postreperfusion. Low-dose testosterone (20 µg/kg) reduced plasma creatinine, increased nitrate/nitrite excretion, increased intrarenal IL-10, and reduced intrarenal TNF-α, whereas 50 µg/kg testosterone failed to reduce plasma creatinine, increased IL-10, but failed to reduce TNF-α. A higher dose of testosterone (100 mg/kg) not only failed to reduce plasma creatinine, but significantly increased both IL-10 and TNF-α compared with other groups. Low-dose nitro-l-arginine methyl ester (1 mg·kg(-1)·day(-1)), given 2 days before I/R, prevented low-dose testosterone (20 µg/kg) from protecting against I/R injury, and was associated with lack of increase in intrarenal IL-10. Intrarenal CD4(+) and CD8(+) T cells were significantly increased with I/R, but were attenuated with low-dose testosterone, as were effector T helper 17 cells. The present studies suggest that acute, low-dose testosterone is protective against I/R AKI in males due to its effects on inflammation by reducing renal T-cell infiltration and by shifting the balance to favor anti-inflammatory cytokine production rather than proinflammatory cytokines.

Pathophysiology of hypertension in response to placental ischemia during pregnancy: a central role for endothelin?

BACKGROUND: Preeclampsia is new-onset hypertension with proteinuria during pregnancy. The initiating event in preeclampsia has been postulated to involve reduced placental perfusion, which leads to widespread dysfunction of the maternal vascular endothelium. OBJECTIVE: The main objective of this brief review was to highlight some of the recent advances in our understanding of the mechanisms whereby the endothelin (ET) system, via ET type A (ETA) receptor activation, modulates blood pressure in preeclamptic women and in animal models of pregnancy-related hypertension. METHODS: This review focused on the role of ET and tumor necrosis factor-alpha (TNF-alpha) in preeclampsia, with emphasis on the pathophysiology of hypertension in response to placental ischemia in animal models of pregnancy. Relevant published data were identified by searching PubMed and supplemented with contributions from our laboratory. RESULTS: Studies in preeclamptic women indicate that their hypertension is associated with increases in ET synthesis. Recent studies in pregnant rats indicate that the ET system is activated in response to reductions in uterine perfusion pressure and to chronic elevations in serum TNF-alpha concentrations. In these 2 animal models, the findings also suggest that ET A receptor activation may play a role in mediating hypertension. CONCLUSIONS: Although recent studies in animal models implicate an important role for the ET system in preeclampsia, the usefulness of selective ET A receptor antagonists for the treatment of hypertension in women with preeclampsia remains unclear. This important question will not be answered until well-controlled clinical studies using specific ET A receptor antagonists are conducted for women with preeclampsia.

Role of sex steroids in modulating tumor necrosis factor alpha-induced changes in vascular function and blood pressure.

BACKGROUND: We previously showed that the infusion of tumor necrosis factor alpha (TNF-alpha) induces hypertension and vascular dysfunction in late pregnant but not virgin rats. In the present study, we tested the hypothesis that levels of ovarian hormones to mimic pregnancy are required for TNF-alpha-induced changes in vascular function and blood pressure in rats. METHODS: Twenty-one-day-release pellets containing 17beta-estradiol, progesterone, or both were implanted in ovariectomized (OVX) rats. Sham OVX rats were used as controls. Twelve days after implantation, TNF-alpha or vehicle was infused via osmotic minipumps (days 12 to 17). On day 18, mean arterial pressure was measured, and animals were sacrificed to assess vascular function. RESULTS: Average estrogen and progesterone levels across all groups were 106 +/- 6 pg/mL and 88 +/- 5 ng/mL, respectively. The level of TNF-alpha was 41 +/- 7 pg/mL compared with OVX rats infused with vehicle (4 +/- 1 pg/mL). The results show that TNF-alpha did not cause elevated mean arterial pressure in OVX rats with increased estrogen, progesterone, or both. Vascular responses to the endothelium-dependent and independent agonists, acetylcholine and sodium nitroprusside, were also unchanged. Phenylephrine-induced contraction was moderately but significantly increased at the highest concentrations (10(-4) M) only in TNF-alpha-infused rats. CONCLUSIONS: These data suggest that increased ovarian hormones to the levels observed during pregnancy are not sufficient to promote TNF-alpha-induced increases in blood pressure or vascular dysfunction.

Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia.

Reduced uterine perfusion pressure during pregnancy is an important initiating event in preeclampsia. Inflammatory cytokines are thought to link placental ischemia with cardiovascular and renal dysfunction. Supporting a role for cytokines are findings of elevated tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 plasma levels in preeclamptic women. Blood pressure regulatory systems (eg, renin-angiotensin system [RAS] and sympathetic nervous system) interact with proinflammatory cytokines, which affect angiogenic and endothelium-derived factors regulating endothelial function. Chronic reductions in placental perfusion in pregnant rats are associated with enhanced TNF-alpha and IL-6 production. Chronic infusion of TNF-alpha or 11-6 into normal pregnant rats significantly increases arterial pressure and impairs renal hemodynamics. TNF-alpha activates the endothelin system in placental, renal, and vascular tissues, and IL-6 stimulates the RAS. These findings suggest that inflammatory cytokines elevate blood pressure during pregnancy by activating multiple neurohumoral and endothelial factors.