Does G protein‐coupled Estrogen Receptor 1 Contribute to Cisplatin‐induced Acute Kidney Injury?
Authors: Gohar Eman Y. , Almutlaq Rawan N. , Fan Chunlan , Balkawade Rohan S. , Butt Maryam K. , Curtis Lisa M. 
Published: May 2022

Cisplatin (Cp) is an effective chemotherapeutic agent used to treat a wide variety of malignancies. Nephrotoxicity is the dose‐limiting side effect of Cp. Acute kidney injury (AKI) following Cp administration is multi‐factorial, involving cellular toxicity, inflammation and proximal tubular injury. Recent evidence points to renal protective actions of G protein‐coupled estrogen receptor 1 (GPER1) in nephropathies evoked by salt loading, hypertension, methotrexate and ischemia reperfusion. Additionally, GPER1 abundance increases after renal ischemia reperfusion injury. However, the involvement of GPER1 signaling in Cp‐induced nephrotoxicity remains unclear. Therefore, this study was designed to test whether genetic deletion of GPER1 exacerbates Cp‐induced AKI in male mice. We subjected 14‐16 weeks‐old male mice homozygous (homo), heterozygous (het) for GPER1 gene and wild‐type (WT) littermates to Cp or saline injections and assessed markers for renal injury on the third day after injections. Specifically, we measured serum creatinine (sCr), urea, neutrophil gelatinase‐associated lipocalin (NGAL), histological indexes of renal tubular injury and abundance of kidney injury molecule‐1 (KIM‐1) and NGAL in the kidney. We determined also serum levels of proinflammatory markers in saline and Cp‐treated mice. A rise sCr was evident in all Cp‐treated mice, compared to saline‐treated mice (WT: 1.72±0.24 vs. 0.12±0.01; het: 1.14±0.30 vs. 0.12±0.01; homo: 1.28±0.31 vs. 0.14±0.01 mg/dl, p<0.0001, p=0.0149, p=0.0028, respectively, n=9‐13). Serum urea and NGAL levels followed the same pattern as sCr. Cp‐induced AKI resulted in comparable histological evidence of injury in all genotypes. Kidney KIM‐1 abundance was higher in saline‐treated homo mice, compared to corresponding WT mice (14.00±2.30 vs. 7.62±0.70 AU, respectively, p=0.0188, n=8, 13). Kidney KIM‐1 abundance was markedly upregulated in response to Cp in all groups, however, no genotypic differences were observed in kidney KIM‐1 in Cp‐treated mice. Cytokine panel assessment demonstrated increased circulating levels of interleukin‐2 (IL‐2), IL‐5, IL‐10 and tumor necrosis factor‐a in Cp‐treated mice. GPER1 deletion lowered plasma IL‐12p70 (p=0.0176). Given the protective role of heme oxygenase‐1 (HO‐1) in Cp‐mediated cell injury, we also investigated genotypic differences in renal HO‐1 abundance. WT and homo mice showed greater renal HO‐1 abundance in response to Cp. Interestingly, renal HO‐1 abundance was lower in Cp‐treated homo, compared to Cp‐treated WT mice (65.74±6.70 vs. 87.83±5.11 AU, respectively, p=0.0083, n=8, 13), despite the lack of genotypic differences in kidney HO‐1 levels in saline‐treated mice. Overall, we demonstrate that GPER1 homo, het male mice and WT littermates elicit comparable renal injury in response to Cp. We show also that GPER1 deletion diminishes HO‐1 induction in response Cp, suggesting that GPER1 may play a permissive role for HO‐1 cytoprotective actions in AKI. GPER1‐induced regulation of HO‐1 after Cp treatment may offer a novel therapeutic target for the treatment of AKI.