The orphan G protein‐coupled receptor 37L1 (GPR37L1) has strong homology with the endothelin‐B receptor but it does not interact with endothelin. GPR37L1 is known to be expressed in several regions in the brain, but its expression profile and function in peripheral tissues are poorly understood. We determined the expression profile of GPR37L1 in mouse organs by RT‐PCR and immunoblot analyses and further used immunohistochemical analyses to locate the sites of GPR37L1 expression within the tissues. Quantitative RT‐PCR revealed that the expression of GPR37L1 was highest in the brain, heart, stomach, testis, and ovary and less in the kidney, liver, lung, spleen, pancreas, and skeletal muscle. Immunohistochemical analyses revealed the expression of GPR37L1 in specific regions within some organs, e.g., neurons in the granular layer of the cerebellum, epithelial cells lining the airway of the lung, epithelial cells lining the gastric mucosa, apical membrane of renal proximal tubule cells (RPTCs), early spermatids in seminiferous tubule of the testis, and granulosa cells in the secondary follicle of the ovary. Transient expression of GPR37L1 in human (h)RPTCs increased sodium transport whereas silencing of GPR37L1 decreased sodium transport. Inhibition of sodium hydrogen exchanger type 3 (NHE3) expression abrogated the GPR37L1‐mediated increase in sodium transport. Renal‐restricted silencing of Gpr37l1 in mice increased urine output and sodium excretion and decreased systolic and diastolic blood pressures. The renal‐selective silencing of GPR37L1 decreased the expression of NHE3 but not the expression of Na+/K+‐ATPase or sodium/glucose cotransporter 2. Over‐expression of GPR37L1 in hRPTCs increased the phosphorylation of ERK1/2 (1.73 ± 0.11‐fold, P<0.05) and AKT (1.89 ± 0.12‐fold, P<0.01) and decreased forskolin‐induced cAMP production (38% ± 4.9). Our findings show that in the kidney GPR37L1 increases luminal RPT sodium transport and blood pressure by increasing NHE3 expression, via the ERK1/2 and AKT pathway and increasing NHE3 function by suppressing cAMP production via Gai. Taken together, these results show that GPR37L1 expressed in RPTCs plays an important role in increasing renal sodium transport; GPR37L1 may be a novel target to design drugs to treat hypertension.Support or Funding InformationUS National Institute of Health R56DK116828, R37HL023081, P01HL074940, R01HL092196, R01DK039308, and R01DK090918, and National Kidney Foundation NKF‐MD‐Mini.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.