{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUromodulin (UMOD) is the gene that encodes Tamm–Horsfall protein, the most abundant protein in normal human urine, which is produced exclusively by epithelial cells of the thick ascending limb of Henle’s loop. Extensive genetic studies have revealed that both rare mutations and common polymorphisms in UMOD are linked with several inherited and complex kidney diseases – including familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease – through mechanisms involving protein misfolding, abnormal trafficking, and altered secretion. These studies demonstrate that UMOD mutations commonly impair endoplasmic reticulum export, leading to intracellular accumulation and reduced apical secretion, while genetic associations indicate that altered uromodulin expression may affect tubular handling of solutes and thereby predispose to age‐related renal injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in maintaining the structural integrity of the tubular lumen, UMOD actively participates in renal ion homeostasis. Functional studies have shown that uromodulin modulates salt reabsorption by interacting with key transport proteins – for example, by enhancing the surface expression and activity of the ROMK2 channel and indirectly promoting the activation of NKCC2, the renal sodium cotransporter. The overexpression of uromodulin, driven by risk variants in its promoter region, has been linked to salt‐sensitive hypertension and age‐associated renal lesions, thereby implicating UMOD as a central regulator of blood pressure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in tubular transport and genetic disease susceptibility, uromodulin has emerged as a multifaceted regulator of renal and systemic homeostasis. When secreted into urine, uromodulin self‐assembles into complex polymeric filaments via a conserved zona pellucida domain, forming a molecular net that aids in the capture and clearance of uropathogens and helps prevent kidney stone formation. Moreover, aggregated uromodulin can act as an endogenous danger signal by activating components of the innate immune system—such as the NLRP3 inflammasome in antigen‐presenting cells—and modulate the number and function of renal mononuclear phagocytes. In clinical contexts, both urinary and serum uromodulin levels have shown promise as biomarkers for predicting chronic kidney disease progression, allograft survival, and cardiovascular risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "48"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "T C Hart, M C Gorry, P S Hart, et al. 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