http://informahealthcare.com/rst ISSN: 1079-9893 (print), 1532-4281 (electronic) J Recept Signal Transduct Res, Early Online: 1–5 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2014.920029

REVIEW ARTICLE

The signaling pathway of uromodulin and its role in kidney diseases Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/11/14 For personal use only.

Song Mao, Aihua Zhang, and Songming Huang Department of Nephrology, Nanjing Children’s Hospital, Affiliated to Nanjing Medical University, Nanjing, China

Abstract

Keywords

The uromodulin (UMOD) is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. UMOD acts as a regulatory protein in health and in various conditions. For kidney diseases, its role remains elusive. On one hand, UMOD plays a role in binding and excretion of various potentially injurious products from the tubular fluid. On the other hand, chronic kidney disease is associated with higher serum levels of UMOD. Signaling pathways might be very important in the pathogenesis of kidney diseases. We performed this review to provide a relatively complete signaling pathway flowchart for UMOD to the investigators who were interested in the role of UMOD in the pathogenesis of kidney diseases. Here, we reviewed the signal transduction pathway of UMOD and its role in the pathogenesis of kidney diseases.

Kidney diseases, signaling pathway, uromodulin

Introduction Uromodulin (UMOD), the most abundant urinary protein in humans (1), excretes through proteolytic cleavage at the luminal cell surface of the thick ascending limb (TAL) of Henle’s loop (2). UMOD contains the most varied array of glycans of human glycoprotein (3), which indicates the capacity for its adhesion to various ligands, such as cytokines, cells, ions, and immunoglobulins. In contrast, the mutations or polymorphisms of UMOD gene can affect UMOD levels leading to an erroneous immune response (4,5), which is closely associated with the risk and progression of kidney diseases. A number of previous studies (6–9) reported that lower urinary UMOD concentrations protected against kidney diseases, higher serum level of UMOD was associated with the risk of chronic kidney diseases, which suggested that UMOD might be a risk factor for kidney diseases. However, another study (10) showed that UMOD gene knockout mice demonstrated difficulty in clearing bacteria from the urinary bladder and was likely to form calcium oxalate stones under experimental hyperoxaluira. An improved understanding of the role of UMOD in various kidney diseases may have important clinical implications provided the possibility that UMOD status may be a biomarker of the susceptibility of kidney diseases. Therefore, we should have a cautious view on the role of UMOD in kidney diseases. Signaling pathways are important factors to clarify the pathogenesis of many diseases (11,12). UMOD regulates a lot

Address for correspondence: Songming Huang, Department of Nephrology, Nanjing Children’s Hospital, Affiliated to Nanjing Medical University, Nanjing 210008, Jiangsu, China. E-mail: [email protected]

History Received 15 March 2014 Revised 27 April 2014 Accepted 28 April 2014 Published online 22 May 2014

of cytokines, and polymorphisms in the UMOD gene have been strongly linked to chronic kidney diseases (13). Meanwhile, many signaling pathways influence the role of UMOD in kidney diseases. Identification of the up/downstream signaling pathways of UMOD will give a new insight to the role of UMOD in kidney diseases. To date, there is rare review to summarize the signaling pathways of UMOD in kidney diseases and its role for the risk and progression of kidney diseases. For a comprehensive understanding of this issue, with the accumulation of available evidence, we, therefore, tried to present the messages of the signaling pathways of UMOD and its role for the risk of kidney diseases. Tumor necrosis factor-a (TNF-a) (14), Interleukin-1 (IL-1) (15), extracellular matrix (16), liver-specific domain-containing protein (LZP) (17), Na+, K+, 2Cl cotransporter (NKCC2) (18), calcium oxalate (CaOx) (19), IgG (20), renal outer medullary potassium channel (ROMK2) (21), bordetella pertussis toxin (22), complement 1q (23), and furosemide (24). These factors might regulate the expression of UMOD and UMOD might regulate the expressions of these factors.

Role of UMOD in signaling pathways There were a lot of studies on the signaling pathways for UMOD in the past. Investigators found that some genes could regulate the expression of UMOD and UMOD could regulate some genes expression (Figure 1). There were some signaling pathways in the upper stream of UMOD as follows: (1) Angiotensin converting enzyme inhibitors (ACEI) lowers the level of urinary UMOD (25).

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J Recept Signal Transduct Res, Early Online: 1–5

Figure 1. Signaling pathways for UMOD in our review.

ACEI, DNA motifs, Sepsis, Rutin

Vitamin E

EG IgG UMOD Transepithelial migration Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/11/14 For personal use only.

Urinary tract diseases

Caveolin-mediated endocytosis

TLR4 NLRP3 Immunity,AKI

N-Glycans

Lactoferrin, Cathepsin G

TRPV5

PNP

IL-1β IFN-γ, IL1α, TNF-α, IL6, CXXL1, L13, T cells, follicle depletion, ovarian degeneration, uric acid, androgen, calcium oxalate, SR, ROMK2, antitrypsin, granulocyte, cystitis, permeability barrier

(2) Vitamin E supplement prevents the loss of osteopontinin (OPN) and UMOD in renal tissues by ethylene glycol (EG) and the reduction in their levels in the urine (26). (3) Conserved DNA upstream motifs and associated transcription factors regulate the expression of UMOD gene (27). (4) Sepsis induces increased expression of UMOD (28). (5) Rutin decreases serum and kidney UMOD levels and increases urine UMOD (29). (6) In a word, only a few identified signaling factors regulate the UMOD levels, further studies should be conducted to identify more factors. There were some signaling pathways in the downstream of UMOD as follows: (1) UMOD triggers IL-1b-dependent immunity via the NLRP3 inflammasome (30). (2) UMOD regulates circulating and renal cytokines (IFN-g, IL1a, TNF-a, IL6, CXXL1, and IL13) by affecting glomerular filtration rate and acting as a urinary cytokine trap (31). (3) UMOD enhances polymorphhonuclear neutrophil phagocytosis (PNP) binding to cell surface-expressed lactoferrin and cathepsin G that activates MAP kinase pathway (32). (4) UMOD links innate immune cell activation with adaptive immunity via a toll-like receptor-4 (TLR4)dependent mechanism (33). (5) UMOD is a costimulator of T cells (34). (6) UMOD upregulates TRPV5 by impairing caveolinmediated endocytosis (35). (7) Overexpression of UMOD-like 1 accelerates follicle depletion and ovarian degeneration (36). (8) Genetic variants of the human UMOD gene regulate transcription and predict plamsa uric acid levels (37). (9) UMOD mutation may be responsible for the enhancement of renal androgen action (38).

(10) UMOD induces the aggregation of calcium oxalate monohydrate (39). (11) UMOD facilitates neutrophil trans-epithelial migration which can be amplified by co-factors such as IgG (40). (12) UMOD protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression (41). (13) Scavenger receptor (SR) expressed by endothelial cells, SR-BI, and SR-AI are cellular receptors for UMOD (42). (14) UMOD carries N-glycans which have a role in the defense against urinary tract diseases (43). (15) UMOD protects urothelial permeability barrier (44). (16) UMOD acts as a general host-defense factor against bacterial cystitis (45). (17) Polarized expression of UMOD by renal tubular epithelial cells activates human granulocytes (46). (18) UMOD promoter directs high-level expression of biologically active human alpha1-antitrypsin into mouse urine (47). (19) UMOD regulates the function of ROMK2 (48). In a word, UMOD induces various inflammatory factors, which in turn mediates the immune response.

Role of UMOD in kidney diseases Healthy individuals excrete about 20–70 mg of UMOD per day, making it the most abundant protein in the urine (49). UMOD forms a gel on the surface of the TAL cells, which is important for water impermeability. It protects against stone disease by preventing aggregation of calcium oxalate crystals (50). UMOD binds to type 1 fimbriae of Escherichia coli and thereby blocks colonization of urothelial cells. High serum UMOD was associated with higher serum levels of the proinflammatory cytokines including TNF-a, IL-1b, IL-6, and IL-8, which were closely associated with

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DOI: 10.3109/10799893.2014.920029

The signaling pathway of uromodulin and its role in kidney diseases

the susceptibility and progression of kidney diseases. Downregulation of synthesis and secretion of UMOD might be a therapeutic option for slowing kidney diseases progression. In contrast, UMOD may have renoprotective properties. Renal ischemia and reperfusion stimulate UMOD expression (51). UMOD knockout mice show more tubular necrosis and inflammation and a greater impairment in renal function than do normal mice (52). In terms of above mentioned, the role of UMOD in kidney diseases is not always consistent. It is speculated that other pathways may interact with UMOD in specific conditions resulting different outcomes. In the past, a number of studies showed that UMOD might play a protective role against the susceptibility and progression of kidney diseases. El-Achkar et al. (53) reported that the increased interstitial presence negatively regulates the evolving inflammatory signaling in neighboring proximal tubules, enhancing kidney recovery. Srichal et al. (54) reported that the apoptosis of the TAL leads to acute kidney injury. El-Achkar et al. (41) reported that UMOD protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Mo et al. (55) reported that the defects in UMOD may contribute to renal calcinosis and stone formation. Bates et al. (10) reported that UMOD knockout mice are prone to urinary tract infection. Serafini-Cessi et al. (43) reported that N-glycans carried by UMOD have a crucial role in the defense against urinary tract diseases. Saemann et al. (34) reported that UMOD links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. Raffi et al. (56) reported that UMOD knockout mice increased stress-induced micturition. Qu et al. (57) reported that upregulation of UMOD expression was early event that occurs prior to podocyte injury. Prajczer et al. (58) reported that patients with both very low urinary and serum UMOD had the highest tubular atrophy scores. In terms of the available evidence, it is reasonable to speculate that UMOD may lower the risk of acute kidney injury, infection. and renal calcinosis. Conversely, a number of studies showed that UMOD was a risk factor for the progression of kidney diseases. Trudu et al. (59) reported that common non-coding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing UMOD expression. Kemter et al. (60) reported that UMOD mutation in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism. Turner et al. (61) reported that UMOD mutations cause familial juvenile hyperuricemic nephropathy. Sato et al. (62) reported that UMOD induced tubulointerstitial nephritis in guinea pigs. It seems that excessive expression and mutation of UMOD are risk factors for the development or progression of chronic kidney diseases. Further studies should be performed to clarify the precise role of UMOD in various kidney diseases.

Conclusions and perspectives Protein–protein interactions of UMOD showed that UMOD interacts with TNF-a, IL-1, extracellular matrix, neutrophils, LZP, NKCC2, CaOx, IgG, ROMK2, bordetella pertussis toxin, complement 1q, and furosemide. There existed a

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signaling pathway between UMOD and TNF-a, IL-1, CaOx, IgG, and ROMK2. However, whether there is a signaling pathway between UMOD and extracellular matrix, neutrophils, LZP, NKCC2, bordetella pertussis toxin, complement 1q and furosemide, and HS, it is not confirmed at the moment. In this review, we do not find the mutual regulation between UMOD and certain signaling factor. Whether the mutual regulation between SDF-1 and other signaling factors exists, it should be confirmed in the future. The signaling pathways of UMOD in the pathogenesis of kidney diseases are complicated. UMOD might play a protective role against acute kidney injury. Meanwhile, it might be a risk factor for the progression of chronic kidney diseases and hereditary kidney diseases. UMOD might play a different role in different conditions. The duration or other signaling pathways might also affect the role of UMOD. In addition, the influence of UMOD gene polymorphisms on the concentration and role of UMOD merits attention. The cells’ culture should be conducted to confirm the role of UMOD in the regulation of other signaling pathways, and whether UMOD affects the susceptibility or progress of kidney diseases by interacting with other signaling factors. The underlying role of biomarker for UMOD in various kidney diseases indicated the possible application of UMOD in some disorders. Also, the association studies should be performed to provide more data proving the role of signaling pathway of UMOD in various kidney diseases and its special association with the kidney compared with other tissues.

Declaration of interest There is no conflict of interest for all authors. This study was supported by Grants from the National Basic Research Program of China 973 Program (nos. 2012CB517602 and 2013 CB 530604), the National Natural Science Foundation of China (nos. 81170635 and 81270785) and the Research and innovation Project for College Graduates of Jiangsu Province, China (Grant number CXLX13_556).

References 1. Serafini-Cessi F, Malagolini N, Cavallone D. Tamm–Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 2003;42:658–76. 2. Hoyer JR, Sisson SP, Vernier RL. Tamm-Horsfall glycoprotein: ultrastructural immunoperoxidase localization in rat kidney. Lab Invest 1979;41:168–73. 3. Pennica D, Kohr WJ, Kuang WJ, et al. Identification of human uromodulin as the Tamm–Horsfall urinary glycoprotein. Science 1987;236:83–8. 4. Wei X, Xu R, Yang Z, et al. Novel uromodulin mutation in familial juvenile hyperuricemic nephropathy. Am J Nephrol 2012;36: 114–20. 5. Han J, Liu Y, Rao F, et al. Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels. Kidney Int 2013;83:733–40. 6. Ko¨ttgen A, Hwang SJ, Larson MG, et al. Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol 2010;21:337–44. 7. Torffvit O, Kamper AL, Strandgaard S. Tamm–Horsfall protein in urine after uninephrectomy/transplantation in kidney donors and their recipients. Scand J Urol Nephrol 1997;31:555–9. 8. Sejdiu I, Torffvit O. Decreased urinary concentration of Tamm– Horsfall protein is associated with development of renal failure and cardiovascular death within 20 years in type 1 but not in type 2 diabetic patients. Scand J Urol Nephrol 2008;42:168–74. 9. Campanello M, Herlitz H, Hultberg B, et al. Serum levels of IgG antibodies against Tamm–Horsfall protein and urinary excretion of

4

10. 11. 12. 13.

Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/11/14 For personal use only.

14.

15.

16. 17.

18.

19. 20. 21.

22. 23.

24. 25. 26. 27.

28. 29. 30. 31.

S. Mao et al. NAG and alpha-1-microglobulin as possible markers for tubular damage in patients with a continent ileal reservoir for urinary diversion. Scand J Urol Nephrol 1997;31:237–43. Bates JM, Raffi HM, Prasadan K, et al. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 2004;65:791–7. Zhou TB, Qin YH. The potential mechanism for the different expressions of gelatinases induced by all-trans retinoic acid in different cells. J Recept Signal Transduct Res 2012;32:129–33. Zhou TB. Signaling pathways of PAX2 and its role in renal interstitial fibrosis and glomerulosclerosis. J Recept Signal Transduct Res 2012;32:285–9. Lhotta K. Uromodulin and chronic kidney disease. Kidney Blood Press Res 2010;33:39–398. Wu CH, Li KJ, Siao SC, et al. The binding affinity and molecular basis of the structure–binding relationship between urinary Tamm– Horsfall glycoprotein and tumor necrosis factor-a. Molecules 2012; 17:11978–89. Muchmore AV. Uromodulin: an immunoregulatory glycoprotein isolated from pregnancy urine that binds to and regulates the activity of interleukin 1. Am J Reprod Immunol Microbiol 1986;11: 89–93. Lambert C, Brealey R, Steele J, et al. The interaction of Tamm– Horsfall protein with the extracellular matrix. Immunology 1993; 79:203–10. Shen HL, Xu ZG, Huang LY, et al. Liver-specific ZP domaincontaining protein (LZP) as a new partner of Tamm-Horsfall protein harbors on renal tubules. Mol Cell Biochem 2009;321: 73–83. Mutig K, Kahl T, Saritas T, et al. Activation of the bumetanidesensitive Na+, K+, 2Cl cotransporter (NKCC2) is facilitated by Tamm–Horsfall protein in a chloride-sensitive manner. J Biol Chem 2011;286:30200–10. Gokhale JA, McKee MD, Khan SR. Immunocytochemical localization of Tamm–Horsfall protein in the kidneys of normal and nephrolithic rats. Urol Res 1996;24:201–9. Rhodes DC, Hinsman EJ, Rhodes JA. Tamm–Horsfall glycoprotein binds IgG with high affinity. Kidney Int 1993;44:1014–21. Renigunta A, Renigunta V, Saritas T, et al. Tamm–Horsfall glycoprotein interacts with renal outer medullary potassium channel ROMK2 and regulates its function. J Biol Chem 2011;286: 2224–35. Menozzi FD, Debrie AS, Tissier JP, et al. Interaction of human Tamm–Horsfall glycoprotein with Bordetella pertussis toxin. Microbiology 2002;148:1193–201. Rhodes DC. Importance of carbohydrate in the interaction of Tamm–Horsfall protein with complement 1q and inhibition of classical complement activation. Immunol Cell Biol 2006;84: 357–65. Dulawa J, Rambausek M, Jann K, et al. Abnormal radiofurosemide binding by Tamm Horsfall glycoprotein of diabetic patients. Diabetologia 1985;28:827–30. Guidi E, Giglioni A, Cozzi MG, et al. Which urinary proteins are decreased after angiotensin converting – enzyme inhibition? Ren Fail 1998;20:243–8 Huang HS, Chen J, Chen CF, et al. Vitamin E attenuates crystal formation in rat kidneys: roles of renal tubular cell death and crystallization inhibitors. Kidney Int 2006;70:699–710. Srivastava R, Micanovic R, El-Achkar TM, et al. An intricate network of conserved DNA upstream motifs and associated transcription factors regulate the expression of uromodulin gene. J Urol 2014. [Epub ahead of print]. doi:10.1016/j.juro.2014.02.095. El-Achkar TM, Huang X, Plotkin Z, et al. Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am J Physiol Renal Physiol 2006;290:1034–43. Chen YS, Hu QH, Zhang X, et al. Beneficial effect of rutin on oxonate-induced hyperuricemia and renal dysfunction in mice. Pharmacology 2013;92:75–83. Darisipudi MN, Thomasova D, Mulay SR, et al. Uromodulin triggers IL-1b-dependent innate immunity via the NLRP3 inflammasome. J Am Soc Nephrol 2012;23:1783–9. Liu Y, El-Achkar TM, Wu XR. Tamm–Horsfall protein regulates circulating and renal cytokines by affecting glomerular filtration rate and acting as a urinary cytokine trap. J Biol Chem 2012;287: 16365–78.

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32. Siao SC, Li KJ, Hsieh SC, et al. Tamm–Horsfall glycoprotein enhances PMN phagocytosis by binding to cell surface-expressed lactoferrin and cathepsin G that activates MAP kinase pathway. Molecules 2011;16:2119–34. 33. Sa¨emann MD, Weichhart T, Zeyda M, et al. Tamm–Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J Clin Invest 2005;115:468–75. 34. Yu CL, Tsai CY, Lin WM, et al. Tamm–Horsfall urinary glycoprotein enhances monokine release and augments lymphocyte proliferation. Immunopharmacology 1993;26:249–58. 35. Wolf MT, Wu XR, Huang CL. Uromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis. Kidney Int 2013;84: 130–7. 36. Wang W, Tang Y, Ni L, et al. Overexpression of uromodulin-like 1 accelerates follicle depletion and subsequent ovarian degeneration. Cell Death Dis 2012;3:e433. 37. Han J, Liu Y, Rao F, et al. Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels. Kidney Int 2013;83:733–40. 38. Takiue Y, Hosoyamada M, Kimura M, et al. Enhancement of androgen action in the kidneys of transgenic mice harboring the mutant human UMOD gene. J Pharmacol Sci 2011;115:383–9. 39. Viswanathan P, Rimer JD, Kolbach AM, et al. Calcium oxalate monohydrate aggregation induced by aggregation of desialylated Tamm–Horsfall protein. Urol Res 2011;39:269–82. 40. Schmid M, Prajczer S, Gruber LN, et al. Uromodulin facilitates neutrophil migration across renal epithelial monolayers. Cell Physiol Biochem 2010;26:311–8. 41. El-Achkar TM, Wu XR, Rauchman M, et al. Tamm–Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am J Physiol Renal Physiol 2008;295:F534–44. 42. Pfistershammer K, Klauser C, Leitner J, et al. Identification of the scavenger receptors SREC-I, Cla-1 (SR-BI), and SR-AI as cellular receptors for Tamm–Horsfall protein. J Leukoc Biol 2008;83: 131–8. 43. Serafini-Cessi F, Monti A, Cavallone D. N-Glycans carried by Tamm–Horsfall glycoprotein have a crucial role in the defense against urinary tract diseases. Glycoconj J 2005;22:383–94. 44. Stein P, Rajasekaran M, Parsons CL. Tamm–Horsfall protein protects urothelial permeability barrier. Urology 2005;66: 903–7. 45. Raffi HS, Bates Jr JM, Laszik Z, et al. Tamm–Horsfall protein acts as a general host-defense factor against bacterial cystitis. Am J Nephrol 2005;25:570–8. 46. Kreft B, Jabs WJ, Laskay T, et al. Polarized expression of Tamm– Horsfall protein by renal tubular epithelial cells activates human granulocytes. Infect Immun 2002;70:2650–6. 47. Zbikowska HM, Soukhareva N, Behnam R, et al. Uromodulin promoter directs high-level expression of biologically active human alpha1-antitrypsin into mouse urine. Biochem J 2002;365:7–11. 48. Renigunta A, Renigunta V, Saritas T, et al. Tamm–Horsfall glycoprotein interacts with renal outer medullary potassium channel ROMK2 and regulates its function. J Biol Chem 2011;286: 2224–35. 49. Fletcher AP, Neuberger A, Ratcliffe WA, et al. Tamm–Horsfall urinary glycoprotein. The chemical composition. Biochem J 1970; 120:417–24. 50. Edyvane KA, Hibberd CM, Harnett RM, et al. Macromolecules inhibit calcium oxalate crystal growth and aggregation in whole human urine. Clin Chim Acta 1987;167:329–38. 51. Yoshida T, Kurella M, Beato F, et al. Monitoring changes in gene expression in renal ischemia-reperfusion in the rat. Kidney Int 2002;61:1646–54. 52. Bachmann S, Mutig K, Bates J, et al. Renal effects of Tamm– Horsfall protein (uromodulin) deficiency in mice. Am J Physiol Renal Physiol 2005;288:559–67. 53. El-Achkar TM, McCracken R, Liu Y, et al. Tamm–Horsfall protein translocates to the basolateral domain of thick ascending limbs, interstitium, and circulation during recovery from acute kidney injury. Am J Physiol Renal Physiol 2013;304:1066–75. 54. Srichai MB, Hao C, Davis L, et al. Apoptosis of the thick ascending limb results in acute kidney injury. J Am Soc Nephrol 2008;19: 1538–46.

DOI: 10.3109/10799893.2014.920029

The signaling pathway of uromodulin and its role in kidney diseases

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55. Mo L, Liaw L, Evan AP, et al. Renal calcinosis and stone formation in mice lacking osteopontin, Tamm–Horsfall protein, or both. Am J Physiol Renal Physiol 2007;293:1935–43. 56. Raffi H, Bates J, Kumar S, et al. Tamm–Horsfall protein knockout mice have increased stress induced micturition. Neurourol Urodyn 2009;28:469–78. 57. Qu Y, Du E, Zhang Y, et al. Changes in the expression of bone morphogenetic protein 7 and Tamm–Horsfall protein in the early stages of diabetic nephropathy. Nephrourol Mon 2012;4: 466–9. 58. Prajczer S, Heidenreich U, Pfaller W, et al. Evidence for a role of uromodulin in chronic kidney disease progression. Nephrol Dial Transplant 2010;25:1896–903.

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59. Trudu M, Janas S, Lanzani C, et al. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med 2013;19:1655–60. 60. Kemter E, Rathkolb B, Rozman J, et al. Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism. Am J Physiol Renal Physiol 2009;297:1391–8. 61. Turner JJ, Stacey JM, Harding B, et al. Uromodulin mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 2003;88:1398–401. 62. Sato K, Oguchi H, Yoshie T, et al. Tubulointerstitial nephritis induced by Tamm–Horsfall protein sensitization in guinea pigs. Virchows Arch B Cell Pathol Incl Mol Pathol 1990;58:357–63.

The signaling pathway of uromodulin and its role in kidney diseases.

The uromodulin (UMOD) is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. UMOD acts a...
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