Pharmacologic and endotoxic reprogramming of renal vasodilatory, inflammatory, and apoptotic blemishes in weaning preeclamptic rats

Preeclampsia (PE) and peripartum sepsis are two complications of pregnancy and are often associated with disturbed renal function due possibly to dysregulated renin angiotensin system. Here we evaluated hemodynamic and renal consequences of separate and combined PE and sepsis insults in weaning mothers and tested whether this interaction is influenced by prenatally-administered losartan (AT1-receptor blocker) or pioglitazone (PPARγ agonist). The PE-rises in blood pressure and proteinuria induced by gestational nitric oxide synthase inhibition (L-NAME, 50 mg/kg/day for 7 days) were attenuated after simultaneous treatment with losartan or pioglitazone. These drugs further improved glomerular and tubular structural defects and impaired vasodilatory responses evoked by adenosinergic (N-ethylcarboxamidoadenosine) or cholinergic (acetylcholine) receptor activation in perfused kidneys of weaning dams. Likewise, treatment of weaning PE dams with a single 4-h dosing of lipopolysaccharides (LPS, 5 mg/kg) weakened renal structural damage, enhanced renal vasodilations and accentuated the upregulated vasodilatory response set off by losartan or pioglitazone. Molecularly, the favorable effect of pharmacologic or endotoxic intervention was coupled with dampened tubular and glomerular expressions of inflammatory (toll-like receptor 4) and apoptotic signals (caspase-3). Our data unveil beneficial and possibly intensified conditioning effect for endotoxemia when combined with losartan or pioglitazone against preeclamptic renovascular dysfunction and inflammation.