SLCO4A1 Governs PGE2-Mediated Natriuresis in the Kidney

Renal sodium retention is a central driver of hypertension and fluid overload. Prostaglandin E2 (PGE2) has long been identified as a potent natriuretic and diuretic factor. However, the mechanisms governing intrarenal PGE2 signaling and tubular sodium transport remain incompletely understood.

Global and renal tubule-specific Slco4a1 knockout mouse, as well as renal tubule-specific Slco4a1 overexpressing mice, were generated to investigate the role of SLCO4A1 in renal sodium and water homeostasis. Computational docking, cellular studies, and in vivo functional analyses were performed to evaluate the role of SLCO4A1in intrarenal distribution of PGE2 and its impact on tubular sodium transport.

SLCO4A1 was predominantly localized to the basolateral membrane of multiple renal tubular epithelial cells. Global and renal tubule-specific Slco4a1 gene deletion increased urine output and sodium excretion and reduced sodium reabsorption across multiple nephron segments in mice. This was accompanied by downregulation of key sodium transporters and channels including SGLT2, NHE3, NKCC2, NCC and ENaC. In contrast, renal tubule-specific overexpression of Slco4a1 displayed an opposite effect. Mechanistically, Slco4a1 deficiency led to accumulation of PGE2 in the kidney interstitum, which suppressed the expression of sodium transporter and channels via the EP receptors. Specifically, EP1 mediated the PGE2-induced suppression of NKCC2, α-ENaC, and β-ENaC. EP2 was responsible for the suppression of NCC, while EP3 was involved in suppressing SGLT2, NHE3 and γ-ENaC.

Collectively, these findings uncovered a previously unrecognized role of SLCO4A1 in regulating intrarenal PGE2 distribution and identified SLCO4A1-PGE2-EP receptor axis in fine-tuning renal tubular sodium transport.