G Protein-coupled Estrogen Receptor 1 and Pregnancy Confer Protection against Renal Injury in Aged Female Mice

Academic Article

Abstract

  • Chronic kidney disease, which is a leading risk factor impacting 1 in 7 American women, is more frequent in aged compared to younger women. Along with the natural aging process, aged women undergo a decline in circulating estrogen level, which is a predisposing factor for renal disease. Estrogen activates the G protein-coupled estrogen receptor 1 (GPER1), which elicits cardiovascular and renal protective actions. Additionally, pregnancy augments GPER1-induced vasodilation in rats. However, there is limited information on the potential interaction between GPER1 and pregnancy in the renal health later in life. We hypothesize that GPER1 signaling, and pregnancy confer protection against renal injury in aged female mice. In our study, 14-16 months-old GPER1 knock-out (KO) and wild-type (WT) female mice with and without a history of former pregnancies were placed into metabolic cages for collection of 24h urine samples. Then, animals were euthanized, plasma and kidneys were harvested for assessment of renal injury. No significant differences in body weight were observed between groups. GPER1 deletion in virgin mice did not impact food intake or urinary Na+ excretion (UNa V). Former pregnancies reduced food intake (p=0.0003) and UNa V (p<0.0001) in GPER1 KO mice. To assess renal function, we measured urinary albumin excretion and plasma creatinine (Cr). GPER1 deletion increased urinary albumin excretion in virgin mice (KO: 16.47±2.08; WT: 6.06±1.04 μg/day; n=6 & 7 respectively; p=0.0005). Interestingly, prior pregnancies eliminated this genotypic difference in albuminuria (KO: 6.12±1.44; WT: 5.79±1.66 μg/day; n=6 & 8 respectively; p=0.986). GPER1 deletion also resulted in higher plasma Cr level in virgin mice (KO: 1.36±0.08; WT: 0.97±0.05 mg/mL; n=6 & 7 respectively; p=0.0018). Prior pregnancies decreased plasma Cr levels in GPER1 KO mice (0.84±0.10 mg/dL, n= 5; p= 0.0012). We also measured urinary excretion of endothelin (ET-1) and aldosterone which are causally linked to renal injury. GPER1 KO elicited greater levels of urinary ET-1 compared to WT virgin mice (0.37±0.06 vs.0.17±0.01 pg/day; n=6 & 7, respectively; p=0.0063). Previous pregnancies lowered urinary levels of ET-1 and aldosterone in GPER1 KO mice (ET-1: p=0.0049; aldosterone: p=0.0099). Furthermore, histological assessment of kidney sections revealed diffuse proliferative glomerulonephritis (GN) with intracapillary hyaline/protein thrombi, in GPER1 KO virgin mice only. No significant acute tubular injury was observed in any group. Further experiments will determine blood pressure and characterize the glomerular lesions evident in aged GPER1 KO virgin mice. Overall, our data demonstrate significant glomerular injury (GN), greater plasma Cr and greater urinary levels of albumin and ET-1 in GPER1 KO virgin mice compared to WT virgin and previously-pregnant GPER1 KO aged mice. The current data suggest that GPER1 and former pregnancies provide protection against glomerular injury in aged females.
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  • The FASEB Journal  Journal
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    Author List

  • Singh R; Almutlaq RN; Fatima H; Gohar EY
  • Volume

  • 36