Figure 3:

Uromodulin location and interaction with key electrolyte transporters. (A) Interaction with sodium transporters. Uromodulin is produced by the epithelial cells lining the TAL and early DCT (DCT1) and remains intracellular until a final cleavage by hepsin releases it in the lumen. In urine, uromodulin mostly forms macromolecular polymers, but can be also found in monomers. In TAL, uromodulin increases Na⁺ reabsorption by activating apical NKCC2 through numerous mechanisms. It mediates vesicular translocation of NKCC2 from the endoplasmic reticulum (ER) to the apical membrane (1), enhances NKCC2 phosphorylation by activating SPAK/OSR1 kinases (2), counteracts the inhibitory effects of TNF-α on NKCC2 (3) and upregulates the expression of ROMK channels by promoting their vesicular translocation from ER to apical membrane (4). In DCT1, uromodulin additionally regulates Na⁺ handling by activating NCC by promoting its phosphorylation through SPAK/OSR1 (5) in addition to likely upregulating ROMK channel expression (6). (B) Interaction with key calcium and magnesium transporters. Uromodulin modulates Mg²⁺ and Ca²⁺ reabsorption by DCT, as uUMOD orchestrates the formation of a urinary multi-protein complex (lattice) that reduces the dynamin-2-dependent endocytosis of TRPM6 (1) and caveolin-mediated endocytosis of TRPV5/6 channels (2) in DCT1 and DCT2; thus, the surface abundance of these transporters is increased.