Abstract

Diabetic kidney disease - remains a challenge clinically. Prostaglandins (PGs), many of which activate E-prostanoid receptor-3 (EP3), have been found to increase in dietetic kidneys; however, how this influences diabetic renal injury through EP3 has not been clearly elucidated. In this study, diabetes was induced in mice with global or myeloid cell-selective Ep3 deficiency ( Ep3 -/- ) and their respective controls by a high-fat diet and streptozocin administration. We showed that myeloid cell-selective Ep3 -/- attenuated renal impairments in diabetic mice similarly as global Ep3 -/- . In accompanying with an increase in PG production and upregulation of Ep3 , increased number of M1 macrophages, inflammation, and multiple forms of regulated cell death (RCD; namely apoptosis, necroptosis, and pyroptosis) were detected in diabetic kidneys. However, all the above-mentioned abnormalities were hardly observed in mice with myeloid cell-selective Ep3 -/- . In vitro experiments further revealed that Ep3 -/- or EP3 antagonism decreased not only macrophage M1-polarization sensitive to Rho kinase inhibition but also the production of PGE 2 in such cells of mice and/or humans. Thus, EP3, whose activation may implicate a self-amplification process, is critically involved in diabetic renal injury via promoting Rho kinase-dependent macrophage M1-polarization to mediate inflammation that may further cause the occurrence of multiple types of RCD, delineating the receptor a promising therapeutic target for diabetic renal injury and diseases with similar mechanisms.