Increasing Nitric Oxide Bioavailability attenuates Vascular Dysfunction and rescues Fetal Growth in female rats with history of acute kidney injury prior to pregnancy

Abstract

Clinical data report a 3-5-fold increase in adverse pregnancy outcomes in women with a history of acute kidney injury (AKI), despite clinical recovery of renal function (creatinine clearance) before pregnancy. We recently showed that female Sprague-Dawley (SD) rats recovered from AKI develop increased blood pressure, uterine artery resistance and decreased fetal growth in pregnancy. Healthy pregnancies are characterized by robust nitric oxide (NO) production and reduction in total peripheral vascular resistance, however, our lab has shown decreased renal nitric oxide synthase (NOS) expression in pregnant rats post-AKI. We, therefore, tested the hypothesis that AKI prior to pregnancy decreases NO which induces endothelial dysfunction and fetal growth restriction. Female SD rats received either 45-min bilateral renal ischemia-reperfusion (AKI) or sham surgery. We utilized sildenafil to increase NO bioavailability. Sham and AKI rats were given vehicle or sildenafil chow 15 days (n=8/grp) post-AKI or sham surgery and mated 15 days later. A separate group of rats (prolonged AKI/Sham) (n=3-6/grp) were mated for pregnancy 6 months post-AKI or sham surgery. Gestational day 1 (GD1) was identified through vaginal smear. On GD19, rats were placed in metabolic cages for urine collection and euthanized on GD20. Pups were weighed and vascular function was assessed via wire myography on 3rd order mesenteric arteries. AKI prior to pregnancy reduced urinary nitrate/nitrite levels assessed via ELISA (3.2±0.9 AKI vs 8.9±1.6 μM/day Sham, *P<0.05) and trended to decrease aortic protein expression of endothelial NOS (eNOS; 0.5±0.1 AKI phospho-/total-eNOS vs 0.8±0.1 Sham, n=3/group, P=0.1) compared to sham pregnant rats. Pup weight decreased in post-AKI pregnant rats (2.14±0.02 g Sham Vehicle vs 2.02±0.05 AKI Vehicle, P=0.06), however, sildenafil restored pup weights in post-AKI rats (2.17±0.04 Sham Sildenafil vs 2.08±0.06 AKI Sildenafil). Pre-pregnancy AKI reduced endothelial-dependent relaxation to acetylcholine (ACh) compared to sham (concentration-response, 1 nM-10 μM, 2-way ANOVA, RM, *P<0.05), indicating endothelial dysfunction. Sildenafil restored endothelial relaxation responses to ACh in post-AKI pregnant rats (P>0.05). None of our groups demonstrated differences in vascular responses to the constrictor phenylephrine or relaxation to sodium nitroprusside. Interestingly, the prolonged 6-month post AKI/Sham group showed increased constrictor responses to phenylephrine (*P<0.05) and KCl (*P<0.05) in post-AKI pregnant rats compared to sham, suggesting prolonged time removed from AKI increases vascular stiffness in pregnancy. Taken together, these data indicate AKI prior to pregnancy induces endothelial dysfunction and that sildenafil, potentially by increasing NO, rescues endothelial function and fetal growth in post-AKI pregnant rats. In addition, our data show that increased recovery time does not ablate vascular dysfunction in pregnancies with history of AKI. R00 HL146948-03 to DM; AHA CDA858380 to JLF; AHA DIVSUP0224732 to DM This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.