The multiple functions of Tamm–Horsfall protein in human health and disease: A mystery clears up

Abstract

Tamm-Horsfall protein (THP) is exclusively produced by renal tubular cells of the distal loop of Henle and is the most abundant urinary protein in mammals. The physiological function of THP has remained elusive for over half a century; however, new lines of research position it as a central antimicrobial molecule combating urinary tract infection (UTI). Furthermore, the genetic basis of familial juvenile hyperuricemic nephropathy (FJHN), glomerulocystic kidney disease (GCKD) and autosomal dominant medullary cystic kidney disease 2 (MCKD2) has been recently attributed to mutations within the THP gene. In these clinical conditions misfolded THP accumulates in the tubular cells, ultimately leading to overt renal insufficiency. UTI is the most common nonepidemic bacterial infection in humans, where both innate and adaptive components of the immune system as well as the bladder epithelium are involved in its prevention and clearance. Since the urogenital tract is devoid of typical physical barriers such as mucus or a ciliated epithelium, soluble mediators with potent anti-bacterial capabilities might exist. Recently, genetic ablation of the THP gene was shown to lead to severe infection and lethal pyelonephritis in experimental models of UTI. In addition, mounting evidence indicates that, beyond simply a direct antimicrobial activity, THP is a potent immunoregulatory molecule that induces specific THP-directed cell-mediated immunity. In light of these novel findings the particular role of THP as a specialized defense molecule in the urinary tract is discussed.

Genetics of Congenital Anomalies of the Kidney and Urinary Tract: The Current State of Play

“…The Uromodulin ( UMOD ) gene encodes the Tamm-Horsfall protein (which is the most abundant physiological urinary protein in humans [99,100] produced by renal tubular cells of the distal loop of Henle) and its mutations have been linked to the pathogenesis of familial juvenile hyperuricemic nephropathy (FJHN), glomerulocystic kidney disease (GCKD) and autosomal dominant medullary cystic kidney disease 2 (MCKD2) [33,101]. Nevertheless, UMOD mutations were not identified in 96 patients with isolated CAKUT, implying that it may represent a very rare etiology for this condition [102].…”

Host antimicrobial proteins as endogenous immunomodulators

“…Interestingly, THP was shown to induce DC maturation via activating a TLR4 dependent cell signaling machinery including activation of IRAK, Akt, p38, ERK1/2 and NFkB. Moreover, we have demonstrated that intravenous challenge with THP rapidly induces the production of THP-specific antibodies and systemic TNF-␣ release, which was completely absent in tlr −/− or myd88 −/− mice, but not in tlr2 −/− or tlr9 −/− mice [69][70][71]. Recent findings revealed that, although THP needs TLR4 to induce signalling, it binds to structures that are distinct from TLR4.…”

“…Under physiological circumstances, these molecules are present at luminal sites only, and therefore do not get in contact with immune cells. However, when translocated from lumen to the interstitium in case of infection these factors display immunomodulatory activities [71,106] (Fig. 2).…”

Uromodulin and Chronic Kidney Disease

“…It protects against stone disease by preventing aggregation of calcium oxalate crystals. Uromodulin binds to type 1 fimbriae of Escherichia coli and thereby blocks colonization of urothelial cells [3] . Uromodulin knockout mice have an impaired capacity to concentrate urine and are prone to renal stone disease and urinary tract infections [4][5][6] .…”