Novel role of urinary urate in renal cystogenesis and water regulation

Mayo Clinic Jacksonville received a $2.97 million Project Grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847), awarded September 1, 2025, with completion targeted for August 31, 2029. The grant funds investigator-initiated biomedical research examining the novel role of urinary urate in renal cystogenesis and water regulation in autosomal dominant polycystic kidney disease (ADPKD). The primary research deliverable involves elucidating mechanisms by which intracellular urate accumulation in renal collecting ducts promotes aquaporin-2 (AQP2) water channel trafficking through AMPK-dependent pathways independent of vasopressin receptor signaling, with the objective of identifying alternative therapeutic strategies to suppress cystogenesis and reduce polyuria associated with current V2 receptor antagonist treatments.

Research activities include mechanistic investigations of urate transporter function (GLUT9B and ABCG2) in water homeostasis and AQP2 regulation, evaluation of ABCG2 inhibition and genetic deletion on urinary concentration capacity in knockout animal models, and characterization of signaling pathways controlling AQP2 phosphorylation and trafficking in cell-based systems. A sub-award to the Veterans Medical Research Foundation of San Diego, formalized January 26, 2026, provides complementary research support under the same investigational framework, expanding the collaborative research capacity for this kidney disease investigation.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), a genetic disorder leading to progressive renal cyst growth, affects 12 million people globally. Arginine vasopressin (AVP) is a key driver of cystogenesis, and in rodent PKD models, the absence of AVP completely prevents cyst formation. Although V2 receptor (V2R) antagonists effectively inhibit cyst growth, their use is limited by significant polyuria (>6 liters/day). An alternative strategy involves enhancing renal water reabsorption to suppress central AVP release. Promising approaches include regulating the water channel aquaporin-2 (AQP2) through pathways independent of V2R. The urate transporters GLUT9B and ABCG2, located in the collecting duct, may play roles in water homeostasis. Notably, hyperuricosuria is associated with hyponatremia and GLUT9 deletion in mice lead to severe polyuria. Additionally, ABCG2 inhibitors might be associated with improved kidney function in ADPKD. Our preliminary findings suggest that intracellular urate accumulation promotes aquaporin-2 (AQP2) exocytosis via AMP-activated protein kinase (AMPK) phosphorylation, independent of V2R/PKA pathways. The overarching hypothesis posits that elevating intracellular urate in collecting ducts promotes AQP2 exocytosis and water reabsorption, suppressing central AVP release and reducing renal cystogenesis in ADPKD. Aim 1 investigates the impact and mechanisms by which urate controls AQP2 trafficking, evaluating the impact of ABCG2 inhibition by KO143 analog and probenecid on urinary concentration in V2R knockout mice, assessing the impact of ABCG2 deletion on urinary concentration capacity and AQP2 phosphorylation, and exploring mechanisms by which increased intracellular urate, due to GLUT9B overexpression and ABCG2 inhibition, controls AQP2, cyclic AMP levels, protein kinase a (PKA), and AMPK activities in V2R-knockdown cell lines. Aim 2 determines the impact and underlying mechanisms of ABCG2 inhibition and genetic deletion in reducing renal cyst growth and mitigating tolvaptan-induced aquaresis in ADPKD, assessing the impact of ABCG2 inhibition and deletion on PKD amelioration in PKD1RC/RC mice, investigating the long-term impact of ABCG2 inhibition and genetic deletion on the anti-cystogenic and aquaretic effects of tolvaptan, and exploring effects of elevated intracellular urate, ABCG2 inhibition, and AMPK inhibitor on in vitro cystogenesis, camp levels, PKA, AMPK, and PDE activities in WT and PKD1 mice and human collecting duct cells. These investigations aim to elucidate the novel interplay between intracellular urate and AQP2-mediated water transport regulation in ADPKD, potentially leading to innovative treatments to slow cystogenesis.