Urinary Excretion of Tamm-Horsfall Protein and Epidermal Growth Factor in Chronic Nephropathy

Torffvit, Ole; Jørgensen, Per Schultz; Kamper, Anne-Lise; Holstein‐Rathlou, N. H.; Leyssac, P. P.; Poulsen, S. S.; Strandgaard, Svend

doi:10.1159/000045020

Cited by 37 publications

(31 citation statements)

References 23 publications

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“…Nevertheless, because reduced urinary excretion of uromodulin has been reported in several nephropathies, it is not clear whether the reduction observed in patients with MCKD2/FJHN may be secondary to distal tubule damage. 74, 75 …”

Section: Fine Mechanisms Related To Delayed Cell Maturation and Storagementioning

confidence: 99%

Uromodulin storage diseases: Clinical aspects and mechanisms

Scolari

Caridi

Rampoldi

et al. 2004

American Journal of Kidney Diseases

125

100

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• The recent discovery of mutations in the uromodulin gene (UMOD) in patients with medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD) provides the opportunity for a revision of pathogenic aspects and puts forth the basis for a renewed classification. This review focuses on clinical, pathological, and cell biology advances in UMOD-related pathological states, including a review of the associated clinical conditions described to date in the literature. Overall, 31 UMOD mutations associated with MCKD2 and FJHN (205 patients) and 1 mutation associated with GCKD (3 patients) have been described, with a cluster at exons 4 and 5. Most are missense mutations causing a cysteine change in uromodulin sequence. No differences in clinical symptoms between carriers of cysteine versus polar residue changes have been observed; clinical phenotypes invariably are linked to classic MCKD2/FJHN. A common motif among all reports is that many overlapping symptoms between MCKD2 and FJHN are present, and a separation between these 2 entities seems unwarranted or redundant. Cell experiments with mutant variants indicated a delay in intracellular maturation and export dynamics, with consequent uromodulin storage within the endoplasmic reticulum (ER). Patchy uromodulin deposits in tubule cells were found by means of immunohistochemistry, and electron microscopy showed dense fibrillar material in the ER. Mass spectrometry showed only unmodified uromodulin in urine of patients with UMOD mutations. Lack of uromodulin function(s) is associated with impairments in tubular function, particularly the urine-concentrating process, determining water depletion and hyperuricemia. Intracellular uromodulin trapping within the ER probably has a major role in determining tubulointerstitial fibrosis and renal failure. We propose the definition of uromodulin storage diseases for conditions with proven UMOD mutations. Am J Kidney Dis 44:987-999.

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Section: Fine Mechanisms Related To Delayed Cell Maturation and Storagementioning

confidence: 99%

Uromodulin storage diseases: Clinical aspects and mechanisms

Scolari

Caridi

Rampoldi

et al. 2004

American Journal of Kidney Diseases

125

100

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“…2B). In the more distal regions resided three stretches of CA (46) repeat and an Alu-Sx repetitive sequence. A computer-assisted sequence search of the 5Ј-flanking region of the mouse THP gene against the Web-based TRANSFEC database and FindPatterns of SeqWeb 1.2 revealed a number of consensusrecognition sequences for known transcription factors.…”

Section: Thp Is Kidney Specific In Micementioning

confidence: 99%

“…Indeed, urinary THP reduction has been associated with certain pathological conditions, including acute tubular necrosis, diabetic nephropathy, hyperprostaglandin E syndrome, and active lupus nephritis (4,23,39,45,47). Although THP has been frequently used as an indicator for renal tubular function (46,57), the mechanisms by which THP gene expression are regulated have not been studied.…”

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confidence: 99%

Isolation of mouse THP gene promoter and demonstration of its kidney-specific activity in transgenic mice

Zhu¹,

Cheng²,

Gao³

et al. 2002

American Journal of Physiology-Renal Physiology

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. Isolation of mouse THP gene promoter and demonstration of its kidney-specific activity in transgenic mice. Am J Physiol Renal Physiol 282: F608-F617, 2002; 10.1152/ajprenal. 00297.2001, the most abundant urinary protein synthesized by the kidney epithelial cells, is believed to play important and diverse roles in the urinary system, including renal water balance, immunosuppression, urinary stone formation, and inhibition of bacterial adhesion. In the present study, we describe the isolation of a 9.3-kb, 5Ј-region of the mouse THP gene and show the highly conserved nature of its proximal 589-bp, 5Ј-flanking sequence with that in rats, cattle, and humans. We also demonstrate using the transgenic mouse approach that a 3.0-kb, proximal 5Ј-flanking sequence is sufficient to drive the kidney-specific expression of a heterologous reporter gene. Within the kidney, transgene expression was confined to the renal tubules that endogenously expressed the THP protein, which suggests specific transgene activity in the thick ascending limb of the loop of Henle and early distal convoluted tubules. Our results establish the kidney-and nephron-segment-specific expression of the mouse THP gene. The availability of the mouse THP gene promoter that functions in vivo should facilitate additional studies of the molecular mechanisms of kidney-specific gene regulation and should provide new molecular tools for better understanding renal physiology and disease through nephron-specific gene targeting.Tamm-Horsfall protein; expression; thick ascending limb of Henle's loop; reporter gene TAMM-HORSFALL PROTEIN (THP), also named uromodulin, is an 85-to 95-kDa glycoprotein that is synthesized by the kidney epithelial cells of all placental mammals (19,20). Within the kidney, THP has been localized by immunohistochemistry and in situ hybridization to the thick ascending limb of Henle's loop (TALH) and the early distal convoluted tubules (2,3,17,27,40). At these locations, THP is believed to be membrane-anchored via its COOH-terminal glycophosphatidylinositol linkage, but the protein can be released into the urine by the action of phospholipases or proteases (7,9,15,28,34). The released THP constitutes the most abundant protein in normal human urine with a daily excretion rate of 50-200 mg (19, 20).Because of its abundance, species conservation, and unique nephron assocation, THP is believed to play critical roles in urinary physiology. First, there has been tremendous interest surrounding the role of THP in immunoregulation, because THP binds avidly to recombinant interleukin (IL)-1, IL-2, tumor necrosis factor (TNF), complement 1q, and immunoglobulins and inhibits lectin-and IL-induced T-cell activation (15,33,51,55). Such inhibitory activity is larely attributed to the oligosaccharid moieties of THP (8,37,43). Because the kidney is the main site of IL catabolism, it has been suggested (15, 20) that THP might act as a potent immunosuppressant. Second, THP has been found to be involved in regulating urinary stone formation, although it is co...

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“…[14] Our results corroborated with several others wherein decreased urinary Uromodulin levels have been reported in CKD patients. [6][7][8][9][10] Pracjczer et al [14] have reported that eGFR correlated positively with urinary Uromodulin levels but negatively with serum Uromodulin levels. However, they have further reported that in a subgroup of patients with lowest eGFR, urinary as well as serum Uromodulin levels were lowest.…”

Section: Discussionmentioning

confidence: 99%

“…[4] Decreased urinary excretion of Uromodulin in parallel with the decrease in glomerular filtration rate (GFR) has been documented. [6][7][8][9][10] Although it is targeted to the apical membrane of TAL cells and secreted into the lumen, detectable levels are also found in venous blood. [11] In order to investigate the potential involvement of Uromodulin in CKD, paired samples of urine and serum were analysed for Uromodulin levels from CKD patients at different stages and correlated with estimated Glomerular Filtration Rate (eGFR) and with renal profile to determine its role in CKD.…”

Section: Introductionmentioning

confidence: 99%

Uromodulin Levels in Chronic Kidney Disease

Shalia

Halankar

2016

Int J of Biomed & Adv Res

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Objectives: Uromodulin is a protein exclusively produced by Kidney in tubular cells lining thick ascending limb (TAL) of the loop of Henle. It has been linked to water electrolyte balance, protective role against urinary tract infections and renal stone formation. To analyse its trend in Chronic Kidney Disease (CKD), its levels were analysed in serum and urine of patients at different stages of CKD. Methods: CKD stage-1 and stage-2 (N=14), Stage-3 (N=24), Stage-4 (N=9), Stage-5 (N= 19) and controls (N=16) were recruited as per the National Kidney Foundation -Kidney Disease Outcome Quality Initiative guidelines. Uromodulin levels were analysed by enzyme linked immunsorbent assay (ELISA). Results: Uromodulin levels both in serum and urine decreased with decreasing kidney function. Bivariate analysis within CKD group showed significant (p=0.001) positive correlation of urinary Uromodulin (spearman correlation [rs]=0.664) and serum Uromodulin (rs=0.855) levels with eGFR and significant (p=0.001) negative correlation of urinary Uromodulin (rs= ̶ 0.872) and serum Uromodulin (rs= ̶ 0.859) with serum creatinine levels. Serum Uromodulin levels in addition showed significant (p=0.001) negative correlation with phosphorus (rs = ̶ 0.523) and corrected calcium phosphorus product (rs= ̶ 0.484). Conclusion: Serum and urine levels of Uromodulin decreased with increasing severity of CKD. Apart from its other protecting role, its reduction may accelerate pathophysiology associated with elevated calcium-phosphorus product in CKD.

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Urinary Excretion of Tamm-Horsfall Protein and Epidermal Growth Factor in Chronic Nephropathy

Cited by 37 publications

References 23 publications

Uromodulin storage diseases: Clinical aspects and mechanisms

Uromodulin storage diseases: Clinical aspects and mechanisms

Isolation of mouse THP gene promoter and demonstration of its kidney-specific activity in transgenic mice

Uromodulin Levels in Chronic Kidney Disease

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