Uromodulin, also known as Tamm-Horsfall protein, is a kidney-specific glycoprotein produced by epithelial cells in the thick ascending limb and early distal convoluted tubule. It plays a multifaceted role in kidney physiology and disease, including regulation of sodium transporters such as NKCC2 and NCC, which are involved in sodium reabsorption. Recent studies suggest a complex interaction between dietary sodium intake, uromodulin, and blood pressure. Uromodulin is the most abundant urinary protein, with significant roles in intracellular, urinary, interstitial, and serum forms. It is involved in various physiological and pathological processes, including kidney function and chronic kidney disease (CKD). Genetic studies have shown that mutations in the UMOD gene are associated with autosomal dominant tubulointerstitial kidney disease (ADTKD) and hypertension. Uromodulin's structure includes multiple domains, with extensive post-translational modifications. It is secreted bilaterally and plays roles in kidney function, including sodium handling, protection against nephrolithiasis, and regulation of magnesium and calcium reabsorption. Uromodulin levels are associated with kidney function and disease outcomes, serving as a biomarker for tubulointerstitial kidney fibrosis. Circulating uromodulin (sUMOD) is a biomarker for tubular integrity and has been linked to renal, cardiovascular, and mortality outcomes. Genetic studies have identified UMOD variants associated with sodium sensitivity and hypertension. Preclinical studies in uromodulin-deficient and overexpressing mice show that uromodulin deficiency leads to decreased BP and salt-wasting, while excess uromodulin causes hypertension. Clinical studies indicate that uromodulin levels are associated with BP response to salt intake and may serve as a prognostic marker and therapeutic target. The role of uromodulin in sodium-sensitive hypertension is supported by genetic and clinical evidence, highlighting its importance in kidney health and disease. Further research is needed to define optimal measurement methods, clarify the role of intracellular uromodulin, and establish consensus on sodium-sensitive hypertension definitions.Uromodulin, also known as Tamm-Horsfall protein, is a kidney-specific glycoprotein produced by epithelial cells in the thick ascending limb and early distal convoluted tubule. It plays a multifaceted role in kidney physiology and disease, including regulation of sodium transporters such as NKCC2 and NCC, which are involved in sodium reabsorption. Recent studies suggest a complex interaction between dietary sodium intake, uromodulin, and blood pressure. Uromodulin is the most abundant urinary protein, with significant roles in intracellular, urinary, interstitial, and serum forms. It is involved in various physiological and pathological processes, including kidney function and chronic kidney disease (CKD). Genetic studies have shown that mutations in the UMOD gene are associated with autosomal dominant tubulointerstitial kidney disease (ADTKD) and hypertension. Uromodulin's structure includes multiple domains, with extensive post-translational modifications. It is secreted bilaterally and plays roles in kidney function, including sodium handling, protection against nephrolithiasis, and regulation of magnesium and calcium reabsorption. Uromodulin levels are associated with kidney function and disease outcomes, serving as a biomarker for tubulointerstitial kidney fibrosis. Circulating uromodulin (sUMOD) is a biomarker for tubular integrity and has been linked to renal, cardiovascular, and mortality outcomes. Genetic studies have identified UMOD variants associated with sodium sensitivity and hypertension. Preclinical studies in uromodulin-deficient and overexpressing mice show that uromodulin deficiency leads to decreased BP and salt-wasting, while excess uromodulin causes hypertension. Clinical studies indicate that uromodulin levels are associated with BP response to salt intake and may serve as a prognostic marker and therapeutic target. The role of uromodulin in sodium-sensitive hypertension is supported by genetic and clinical evidence, highlighting its importance in kidney health and disease. Further research is needed to define optimal measurement methods, clarify the role of intracellular uromodulin, and establish consensus on sodium-sensitive hypertension definitions.