Sildenafil Citrate Does Not Reprogram Risk of Hypertension and Chronic Kidney Disease in Offspring of Preeclamptic Pregnancies in the Dahl SS/Jr Rat

Abstract

Background: Preeclampsia is a disorder of pregnancy with high disease and economic burdens in the United States. Evidence supporting longstanding effects of preeclampsia on the offspring of affected pregnancies is high, but the effects of current antihypertensive therapies for preeclampsia on cardio-renal outcomes are largely unknown. The purpose of this study was to test the hypothesis that sildenafil citrate, a phosphodiesterase-5 inhibitor, reprograms the risk of hypertension and kidney disease in offspring of preeclamptic pregnancies by altering responses to secondary stressors. Methods: Dahl SS/Jr rats on a 0.3% NaCl diet were mated. At gestational day 10, pregnant dams were randomized to vehicle diet or diet with sildenafil (50 mg/kg/day), which was continued until birth. Pups were weaned at four weeks of age and allowed to age on a 0.3% NaCl diet until three months of age. At this point, pups were randomized into three groups: baseline or no intervention, 2% NaCl diet challenge for four weeks, or a subpressor infusion of angiotensin II (200 ng/kg/min) for two weeks. Results: There were no differences among maternal treatment groups at baseline. Upon introduction of 2% NaCl diet, male offspring of SLD-treated dams exhibited an attenuated rise in BP; however, this protection was not observed during Ang II infusion. Conclusions: Our findings indicate that intrapartum sildenafil does not reprogram the risk of hypertension and kidney disease in offspring of preeclamptic pregnancies. (BP) during childhood and into adulthood [3,4]. This hypothesis, the Developmental Origins of Health and Disease (DOHaD) theory, proposes that an adverse intrauterine environment (insufficient nutrition or blood flow to the fetus) results in epigenetic changes that alter metabolism and physiologic response mechanisms, throughout the life of the offspring [5,7]. Further studies and meta-analyses showed that children born after preeclamptic pregnancies are at greater risk for vascular diseases such as hypertension and stroke [23,24,33]. While several proposed mechanisms for this link have gained evidentiary support [12,13,32,37], the exact nature of this pathogenesis remains unknown, so no potential therapeutic interventions have been shown. Despite increasing research for potential preeclampsia treatments, the current standard of care is limited to careful monitoring, limited antihypertensive treatment, magnesium sulfate infusion for prevention of eclamptic seizures, and early delivery [1]. While continued gestation is usually beneficial for fetal development, continued exposure to an intrauterine environment with suboptimal nutrition conveys additional risk [2,6].Experimental therapies currently being tested include antioxidants (ex.

Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model

“…Expression analysis was performed on select candidate genes residing within identified loci using a next generation sequencing approach as previously described 27 . RNA was isolated from kidney collected from most of the HS rats that had both phenotype and genotype information (n = 240) using an automated KingFisher Flex nucleic acid system along with KingFisher Pure RNA Kit.…”