G Protein-Coupled Estrogen Receptor 1 Enhances DNA Damage Response in the Aging Female Kidney

Estrogen, a female sex hormone, activates several receptors including the G protein-coupled estrogen receptor 1 (GPER1), which elicits protective actions within the kidney. We recently found that genetic deletion of GPER1 promotes renal tubular injury in aged female mice. However, little is known about the impact of GPER1 on renal aging. It is well established that the Sirtuins (Sirt) family and AMP-activated protein kinase (AMPK) play key roles in promoting longevity by facilitating efficient DNA repair mechanisms and are implicated in the female protection against kidney injury. Thus, the current study aimed to investigate the effect of GPER1 deletion on the expression of Sirt 6 and AMPK in the kidneys of aged female mice. We hypothesized that GPER1 promotes the expression of DNA repair genes in the aged female kidney. To test the hypothesis, renal cortex was collected from female wild-type (WT) and global genetic GPER1 knockout (KO) mice (15–17 months of age) and assessed for Sirt 6 and AMPK mRNA expression by RT-PCR. Sirt 6 mRNA expression in kidneys obtained from KO mice was lower when compared to WT mice (0.68 ± 0.06 vs. 1.00 ± 0.09 fold change; p = 0.01; n = 6/group). KO mice elicited a trend towards lower AMPK mRNA expression compared to WT mice (0.76 ± 0.08 vs. 1.00 ± 0.08 fold change; p = 0.07; n = 6-7/group), however, this did not reach statistical significance. It is evident that Sirt 6 works cooperatively with the H2A histone family member X (H2AX) gene in the regulation of DNA damage response, so we extended the study to assess the renal expression of H2AX. Similarly, we found that the KO mice had markedly lower renal H2AX mRNA expression compared to WT mice (0.49 ± 0.06 vs. 1.00 ± 0.12 fold change; p = 0.04; n = 6-7/group). The current results show that GPER1 deletion downregulated Sirt 6 and H2AX expressions in the aged female kidney. These findings indicate that GPER1 promotes key pathways essential for DNA damage repair and cell survival in the aged female kidney, which may contribute to kidney longevity. GPER1-mediated regulation of key longevity genes may contribute to premature renal aging in postmenopausal women. NIH/NHLBI R01HL171122-01 to EYG This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.