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.