Specific HIF-2α (Hypoxia-Inducible Factor-2) Inhibitor PT2385 Mitigates Placental Dysfunction In Vitro and in a Rat Model of Preeclampsia (RUPP)

Although nonsteroidal antiinflammatory drugs (NSAIDs) are frequently used for fever and pain during pregnancy, their possible interaction with perinatal renal injury induced by preeclampsia (PE) has not been addressed. Here, studies were undertaken in the N(gamma)-nitro-l-arginine methyl ester (l-NAME) PE model to assess the influence of gestational NSAIDs on renal damage in weaning dams. PE-evoked increments and decrements in urine protein and creatinine clearance, respectively, were intensified by celecoxib and weakened by diclofenac or naproxen. Naproxen also improved renal cloudy swelling, necrosis, and reduced glomerular area evoked by PE. The concomitant rises in renal expression of markers of oxidative stress (NOX2/4), extracellular matrix metaloproteinase deposition (MMP9), and prostanoids (PGE2, PGF2α, TXA2) were all more effectively reduced by naproxen compared with celecoxib or diclofenac. Western blotting showed tripled expression of mitogen-activated protein kinases (MAPKs; p-p38, p-JNK1, p-ERK1, p-ERK2) in PE kidneys that was overturned by all NSAIDs, with naproxen producing the largest drop in p-ERK2 expression. The PE-provoked elevation in renal expression of autophagic marker LC3 was reduced by naproxen and diclofenac, but not celecoxib. The data suggests superior effect for naproxen over other NSAIDs in rectifying preeclamptic renal injury and predisposing inflammatory, oxidative, autophagic, and fibrotic signals.

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ERAP1 shows distinct regulatory mechanisms on blood pressure modulation between males and females

Ding

Heydarpour

Gomez

et al. 2023

Preprint

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Background: Ang II plays important roles in controlling stability of BP. ERAP1 can regulate BP by reducing the level of Ang II. However, the downstream mechanisms of activated Ang II which are activated by ERAP1 deletion have not been identified. Methods: Tail-cuff was used to measure BP in the ERAP1 deficient and wt mice. Ang II were evaluated by LC-MS. Aldo were measured with ELISA kits. PAH clearance was collected and used to calculate renal plasma flow (RPF) . RT-qPCR, immunochemistry staining, and bulk RNA sequencing were applied to identify the mechanisms. Two medications (Enalapril and Amlodipine) were used as control. BP data was collected to examine the influence of ERAP1 rs30187 risk allele carriers to SSBP. Results: Ang II were upregulated and induced hypertension in ERAP1 deficient mice. BP did not show sex differences, while Ang II expression exhibited sex dimorphism. Along with an increase of Aldo levels, the expressions of ERAP1 and CYP11B2 were co-knockdown in ZG cells in male ERAP1+/- mice. Different activated genes were further detected. While in ERAP1+/- females, decreased RPF and lower ERAP1 and CD31 expressions in endothelial cells were observed. Enalapril took effects in dropping BP and decreasing Aldo production. Smaller BP decline and no difference of RPF in females was confirmed in Amlodipine group. People <51 years old with the ERAP1 rs30187 risk allele exhibited increased SSBP. Conclusions: ERAP1 exerted BP control by regulating Ang II. In male ERAP1+/- mice, the primary regulated mechanism occurred in adrenals, where overexpressed Ang II targeted ZG cells, activated Aldo production pathway. In female ERAP1+/- mice, the prominent mechanism was dependent on the alterations of vascular, elevated Ang II downregulated endothelial cells' proliferation, decreased RPF and exacerbated renal vascular function. Enalapril had stronger effects in regulating RAAS and Amlodipine played important roles in relaxing the vessels.

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Specific HIF-2α (Hypoxia-Inducible Factor-2) Inhibitor PT2385 Mitigates Placental Dysfunction In Vitro and in a Rat Model of Preeclampsia (RUPP)

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References 77 publications

Increased uterine arterial tone, stiffness and remodeling with augmented matrix metalloproteinase-1 and -7 in uteroplacental ischemia-induced hypertensive pregnancy

Increased uterine arterial tone, stiffness and remodeling with augmented matrix metalloproteinase-1 and -7 in uteroplacental ischemia-induced hypertensive pregnancy

The suppression of MAPK/NOX/MMP signaling prompts renoprotection conferred by prenatal naproxen in weaning preeclamptic rats

ERAP1 shows distinct regulatory mechanisms on blood pressure modulation between males and females

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