The Effect of Palosuran on Preeclamptic Pregnant Rats and Their Offspring

Project no. 23093 · Status: Kapanmış (Yayın bekleniyor) · 2021

Summary

Preeclampsia affects approximately 5-7% of all pregnancies worldwide. It is a major cause of maternal and perinatal mortality and morbidity. Preeclampsia is defined as new onset gestational hypertension with proteinuria, maternal organ dysfunction or uteroplacental dysfunction after 20 weeks’ gestation.The administration of N-nitro-L-arginine-methyl ester (L-NAME) to laboratory animals is a well known experimental hypertension, cardiovascular and kidney disease model. It has been show that inhibition of NOS in rats by L-NAME at different gestational stages led to preeclampsia-like symptoms such as hypertension, proteinuria and IUGR.Urotensin II (U-II) is currently the most potent vasoconstrictor identified. It is mainly affecting myocardial and arterial smooth muscle cells through a G-protein coupled receptor named GPR14. U-II and its receptor are mostly expressed in the cardiovascular and central nervous systems, but also in the endocrine system, placenta and the kidneys. In some studies on preeclamptic women, it has been demonstrated that U-II levels in plasma and UTR levels in placenta were increased. It has been shown that plasma and placenta U-II levels and mean arterial pressure are positively correlated in preeclamptic women. Palosuran is a non-peptide, selective U-II receptor antagonist. Its therapeutic role in diseases such as nephrotoxicity, renal ischemia and pulmonary arterial hypertension has been studied in animals.In our study, rats were divided into 4 groups: Control group (rats treated with intraperitoneal saline starting from gestational day 9 [GD9], n=10), Palosuran group (rats treated with Palosuran [75 mg/kg/twice a day] starting from GD14, n=8), L-NAME group (rats treated with intraperitoneal L-NAME [150 mg/kg] starting from GD9, n=8), Treatment group (rats treated with intraperitoneal L-NAME [150 mg/kg] starting from GD9 and Palosuran [75 mg/kg/twice a day] starting from GD14, n=8). All rats were mated at the appropriate time of the estrous cycle and pregnancy was determined by the presence of sperm in the vaginal smear. Throughout pregnancy, maternal blood pressure was measured by noninvasive tail cuff methode and urine samples were collected by metabolic cage. Both processes were repeated three times. After cesarean, maternal serum creatinine, BUN, AST, ALT, hemoglobin, hematocrit, platelet, sFlt-1, PlGF and U-II levels were measured. Histological and immunohistochemical (eNOS, iNOS, nNOS and UTR) examinations were performed on the maternal kidney, liver, placenta, umbilical cord and offspring brain.Administration of palosuran improved L-NAME induced hypertension and proteinuria. Serum creatinine and ALT increased in the L-NAME group. BUN, AST, hemoglobin, hematocrit, platelet count, sFlt-1, PlGF and sFlt1/PLGF were similar in all groups. Urotensin II level increased in the L-NAME, but decreased in the Treatment group. There were no significant differences between the groups in terms of the number of offspring, placental weight and kidney weight. Pup weight decreased in the L-NAME group compared to the Control and Palosuran groups.In histological examinations, it was observed that the histological structure was impaired in the kidney, placenta, liver and pup brain in the L-NAME group, but improved in the Treatment group. In immunohistochemical analysis, eNOS expression in the placenta, kidney and liver decreased in the L-NAME group, but increased with Palosuran administration. It has been shown that iNOS expression increased with L-NAME but decreased with Palosuran. nNOS expression decreased with L-NAME in the cerebral cortex, hippocampus and cerebellum but increased in the Treatment group.As a result, findings have been obtained that Palosuran has positive effects on pregnant women and offspring in preeclampsia. Further studies are needed to better understand the underlying mechanisms and to use Palosuran therapeutically in preeclampsia.

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