Role of Uromodulin in Salt-Sensitive Hypertension

Abstract

The exclusive expression of uromodulin in the kidneys has made it an intriguing protein in kidney and cardiovascular research. Genome-wide association studies discovered variants of uromodulin that are associated with chronic kidney diseases and hypertension. Urinary and circulating uromodulin levels reflect kidney and cardiovascular health as well as overall mortality. More recently, Mendelian randomization studies have shown that genetically driven levels of uromodulin have a causal and adverse effect on kidney function. On a mechanistic level, salt sensitivity is an important factor in the pathophysiology of hypertension, and uromodulin is involved in salt reabsorption via the NKCC2 (Na⁺-K⁺-2Cl^- cotransporter) on epithelial cells of the ascending limb of loop of Henle. In this review, we provide an overview of the multifaceted physiology and pathophysiology of uromodulin including recent advances in its genetics; cellular trafficking; and mechanistic and clinical studies undertaken to understand the complex relationship between uromodulin, blood pressure, and kidney function. We focus on tubular sodium reabsorption as one of the best understood and pathophysiologically and clinically most important roles of uromodulin, which can lead to therapeutic interventions.

Keywords: blood pressure; kidney; loop of Henle; sodium; uromodulin.

Figure 1.

Uromodulin gene to protein. The 20 kb gene of UMOD is translated to 640 amino acid protein by 10 exons. Major single nucleotide polymorphisms are represented on the gene. The protein structure represented in image consists of an N-terminal signal peptide (1–24), 4 epidermal growth factor-like domains (I, II, III, and IV), a domain rich in 8 cysteine (D8C), the 2 zona pellucida domain (ZP-N and ZP-C), and a glycosylphosphatidylinositol (GPI) anchoring site.

Figure 2.

Uromodulin regulates salt reabsorption via NKCC2 (Na⁺-K⁺-2Cl⁻ cotransporter). Two mechanistic approaches studied through preclinical models show that uromodulin regulates NKCC2 (Na⁺-K⁺-2Cl⁻ cotransporter) via activation (phosphorylation) of SPAK (STE20/SPS1–related proline/alanine-rich kinase) and OSR1 (oxidative stress response 1 kinase), and inhibition of TNF (tumor necrosis factor)-alpha. The red and green dotted arrow represents indirect signaling pathway for inhibition and activation, respectively.

Figure 3.

Umod^−/− knockout mice are not sensitive to NaCl-induced changes in blood pressure. Wild-type (WT) mice have significantly increased (A) systolic blood pressure (SBP) and (B) pulse pressure (PP) compared with the Umod^−/−. C and D, There is a leftward shift in the chronic renal function curves (SBP, mean arterial pressure [MAP]) in Umod^−/− mice compared with the WT animals. Adapted from Graham et al with permission. Copyright ©2014, Wolters Kluwer Health, Inc.

Figure 4.

Uromodulin in precision medicine. The figure represents the rationale for the clinical trial (https://www.clinicaltrials.gov; Unique identifier: NCT03354897) for understanding the influence of UMOD variant on blood pressure (BP) for personalized treatment. eGFR indicates estimated glomerular filtration rate.