Tamm-Horsfall protein/uromodulin deficiency elicits tubular compensatory responses leading to hypertension and hyperuricemia

Am J Physiol Renal Physiol. 2018 Jun 1;314(6):F1062-F1076. doi: 10.1152/ajprenal.00233.2017. Epub 2018 Jan 10.


Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, and confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses, resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricemia.

Keywords: NKCC2; Tamm-Horsfall protein; hyperuricemia; lipid rafts; thick ascending limb; uromodulin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Blood Pressure
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Disease Models, Animal
  • Diuretics / pharmacology
  • Genetic Predisposition to Disease
  • Hypertension / genetics
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Hyperuricemia / genetics
  • Hyperuricemia / metabolism*
  • Hyperuricemia / physiopathology
  • Kidney / metabolism*
  • Kidney / physiopathology
  • Kidney / ultrastructure
  • Kidney Diseases / drug therapy
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism*
  • Kidney Diseases / physiopathology
  • Male
  • Membrane Microdomains / metabolism
  • Mice, 129 Strain
  • Mice, Knockout
  • Monocarboxylic Acid Transporters
  • Oliguria / genetics
  • Oliguria / metabolism
  • Oliguria / physiopathology
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism
  • Phenotype
  • Renin-Angiotensin System
  • Sodium-Hydrogen Exchanger 3 / genetics
  • Sodium-Hydrogen Exchanger 3 / metabolism
  • Solute Carrier Family 12, Member 1 / genetics
  • Solute Carrier Family 12, Member 1 / metabolism
  • Urination* / drug effects
  • Uromodulin / deficiency*
  • Uromodulin / genetics


  • Cation Transport Proteins
  • Diuretics
  • Monocarboxylic Acid Transporters
  • Organic Anion Transporters
  • Slc12a1 protein, mouse
  • Slc22a12 protein, mouse
  • Slc5a8 protein, mouse
  • Slc9a3 protein, mouse
  • Sodium-Hydrogen Exchanger 3
  • Solute Carrier Family 12, Member 1
  • Umod protein, mouse
  • Uromodulin