Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by Slc38a2-gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that Slc38a2-knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that Slc38a2 is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.

Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that VSMC-specific deletion of EP4 (VSMC-EP4) ameliorated, while VSMC-specific overexpression of human EP4 promoted, neointimal hyperplasia in mice subjected to femoral artery wire injury or carotid artery ligation. In vitro studies revealed that pharmacological activation of EP4 promoted, whereas inhibition of EP4 suppressed, proliferation and migration of primary-cultured VSMCs. Mechanically, EP4 significantly increased the protein expression of tenascin C (TN-C), a pro-proliferative and pro-migratory extracellular matrix protein, at the translational level. Knockdown of TN-C markedly suppressed EP4 agonist-induced VSMC proliferation and migration. Further studies uncovered that EP4 upregulated TN-C protein expression via the PKA/mTORC1/Ribosomal protein S6 (rpS6) pathway. Together, our findings demonstrate that VSMC EP4 increases TN-C protein expression to promote neointimal hyperplasia via the PKA-mTORC1-rpS6 pathway. Therefore, VSMC EP4 may represent a potential therapeutic target for vascular restenosis.

Hypertension remains a major global health burden with limited effective treatment options. In the present study, the sodium-dependent neutral amino acid transporter SLC38A2 was identified as a regulator of blood pressure (BP) through modulating endothelial nitric oxide (NO) signaling. Here, we show that mice with global and endothelial cell (EC)–specific Slc38a2 gene knockout ( Slc38a2 ^△EC ) exhibited reduced blood pressure compared with wild-type controls. Single-cell RNA sequencing analysis revealed enhanced NO biosynthesis in the ECs of the Slc38a2 ^△EC mice. Blockade of endothelial SLC38A2 by its inhibitor methylaminoisobutyric acid (MeAIB) increased NO production through activating the protein kinase B (AKT)–endothelial NO synthase (eNOS) pathway by inhibiting EC uptake of glutamine. Moreover, MeAIB lowered blood pressure in both high-salt and deoxycorticosterone acetate (DOCA)–induced hypertensive mouse and rat models. Last, in two independent population cohorts including a Chinese cohort established by our group and a European cohort from the UK Biobank, the SLC38A2 rs1873793 variant was associated with increased risk of hypertension under a recessive model. Collectively, our findings demonstrate that targeting SLC38A2 may represent a therapeutic target for the treatment of hypertension.

The mechanisms by which metabolic stress drives epigenetic dysregulation and fibrosis in chronic kidney disease (CKD) remain incompletely understood. Using quantitative histone proteomics in murine fibrosis models, we uncovered a selective increase in histone H3 lysine 27 acetylation (H3K27ac) as a conserved epigenetic feature. Unbiased metabolomics revealed citrate accumulation, nominating ATP‐citrate lyase (ACLY) as a driver of acetyl‐CoA‐dependent histone acetylation. In murine models of folic acid and unilateral ureteral obstruction, ACLY expression, acetyl‐CoA levels, and H3K27ac were increased in injured kidneys. Tubule‐specific Acly deletion reduced acetyl‐CoA, H3K27ac, and attenuated tubulointerstitial fibrosis. Chromatin accessibility profiling revealed that loss of Acly decreased accessibility at pro‐inflammatory loci, including Jak1 and Jak2 , with reduced transcriptional output. These transcriptional and epigenetic signatures were observed in human CKD samples, where higher ACLY expression correlated with worse kidney function and increased JAK1/2 expression. Notably, ACLY inhibitors, including bempedoic acid and BMS‐303141 recapitulated the antifibrotic effects of Acly deletion in vivo in mice, supporting the therapeutic repurposing of ACLY inhibitors for CKD. Together, our findings position ACLY as a key metabolic‐epigenetic checkpoint of kidney fibrosis and a promising, druggable target for halting CKD progression.

Activation of PXR enhances urine concentration, whereas PXR deficiency diminishes this capacity. PXR is coexpressed with AVP in the hypothalamus, where it upregulates AVP transcription to promote renal water reabsorption. These findings reveal a novel role for PXR in regulating urinary concentration and propose its potential as a therapeutic target for water metabolism disorders, such as diabetes insipidus.

Background: Renal sodium retention is a central driver of hypertension and fluid overload. Prostaglandin E ₂ (PGE ₂ ) has long been identified as a potent natriuretic and diuretic factor. However, the mechanisms governing intrarenal PGE ₂ signaling and tubular sodium transport remain incompletely understood. Methods: 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 PGE ₂ and its impact on tubular sodium transport. Results: 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 PGE ₂ in the kidney interstitum, which suppressed the expression of sodium transporter and channels via the EP receptors. Specifically, EP ₁ mediated the PGE ₂ -induced suppression of NKCC2, α-ENaC, and β-ENaC. EP ₂ was responsible for the suppression of NCC, while EP ₃ was involved in suppressing SGLT2, NHE3 and γ-ENaC. Conclusions: Collectively, these findings uncovered a previously unrecognized role of SLCO4A1 in regulating intrarenal PGE ₂ distribution and identified SLCO4A1-PGE ₂ -EP receptor axis in fine-tuning renal tubular sodium transport.