Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-β1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-β1 pathway may be an effective therapeutic strategy for renal fibrosis.
A subset of ANGII and SHAM animals received daily 1% w/v MgSO 4 drinking water from GD0.5 (n = 4/group; SHAM/ANGII+MgSO 4 ). Blood pressure, cardiac function, and uteroplacental blood flow were measured by tail-cuff plethysmography and Doppler ultrasound pre-pregnancy (PP) and at GD6.5, 12.5, and 18.5. Urine samples were collected by metabolic cage at PP, GD6.5, and GD18.5 for measurement of proteinuria. Fetal and placental measurements were collected at sacrifice.
Results: ANGII shows features consistent with SPE in humans via decreased stroke volume and elevated blood pressure alongside decreased fetal and placental weights vs SHAM (****p < 0.0001, **p < 0.01, *p < 0.05). Additionally, ANGII resulted in significantly altered fluid homeostasis and proteinuria vs SHAM (****p < 0.0001, ***p < 0.001, **p < 0.01). ANGII+MgSO 4 showed a decrease in blood pressure vs ANGII (**p < 0.01). Treatment with MgSO 4 had no significant effect on cardiac function, though there was a trend towards improvement in delta cardiac output. Neither ANGII nor additional MgSO 4 altered indices of uteroplacental flow vs ANGII or SHAM. ANGII+MgSO 4 exhibited a significant reduction in proteinuria vs ANGII (*p < 0.05) as well as improvements in fluid homeostasis. Both fetal and placental weights were significantly reduced in ANGII+MgSO 4 vs SHAM (**p < 0.001) indicating a detrimental effect.Conclusions: These results suggest 1% w/v MgSO 4 may be beneficial as a preventative therapeutic in pregnancies affected by super-imposed pre-eclampsia for maternal but not fetal outcomes. Further work is needed to elucidate the effects of MgSO 4 in the context of hypertensive pregnancy.
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