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Uromodulin and kidney disease: a new entry for an old molecule MCKD/FJHN Italian Consortium Gian Marco Ghiggeri Lyon ESPN 2008.

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Presentation on theme: "Uromodulin and kidney disease: a new entry for an old molecule MCKD/FJHN Italian Consortium Gian Marco Ghiggeri Lyon ESPN 2008."— Presentation transcript:

1 Uromodulin and kidney disease: a new entry for an old molecule MCKD/FJHN Italian Consortium Gian Marco Ghiggeri Lyon ESPN 2008

2 Uromodulin Most abundant protein in human urine ( mg/day) Glomerulus Henles loop Collecting duct descending limb ascending limb proximal tubule distal tubule Exclusively expressed in TAL and DCT Dahan et al., J Am Soc Nephrol 2003 Initially described by Tamm and Horsfall in 1950

3 150 5 kDa 49 Non linear pH

4 Tamm Horsfall Glycoprotein J Exp Med Jan;95(1): J Exp Med Jan;95(1):71-97 Igor TAMM and Frank L. Horsfall. Characterization and separation of an inhibitor of viral hemagglutination present in urine. Proc Soc Exp Biol Med May;74(1):106-8

5 Uromodulin structure Jovine et al.,Nat Cell Biol 2002 ZP is a large domain, containing around 260 aa, including 8(10) conserved Cys residues, which are involved in disulphide bond formation. Found in a variety of receptor-like eukaryotic glycoproteins (mouse sperm receptors ZP1, ZP2, ZP3; alpha-tectorin) ZP domain proteins almost invariably contain single transmembrane domains or GPI anchors that are missing from the secreted mature proteins Responsible for the ability of ZP domain proteins to assemble into filaments ZP domain IIII YYYY Y YY D8CII

6 cf 568 EVYLCDIINEKCKPTCSGTRFRSGGIIDQSRVLNLGPITRKNVQAVVSRAASSSLGFLKVCLPLLLSATLTLMFQ 642 bt 569 EVYLCDTVNEKCRPTCPETRFRSGSIIDQTRVLNLGPITRKGGQAAMSRAAPSSLGLLQVWLPLLLSATLTLMSP 643 hs 567 EVYLCDTMNEKCKPTCSGTRFRSGSVIDQSRVLNLGPITRKGVQATVSRAFSS-LGLLKVWLPLLLSATLTLTFQ 640 mm 568 EVYLCDSTSEQCKPTCSGTRFRSGNFIDQTRVLNLGPITRQGVQASVSKAASSNLRLLSIWLLLFPSATLIFMVQ 642 rn 570 EVYLCDTMSEQCKPTCSGTRYRSGNFIDQTRVLNLGPITRQGVQASVSKAASSNLGFLSIWLLLFLSATLTLMVH 644 ******.*:*:***. **:***..***:**********:. ** :*:*.* * :*.: * *: **** : ZP domain IIII YYYY Y YY D8CII Santambrogio et al.,Biochem Biophys Res Comm 2008 Uromodulin structure GPI anchor

7 Uromodulin function Mo et al, Am J Physiol Renal Physiol, 2003 Urothelial defence against infections Urothelial defence against calcium oxalate crystals- induced damage Urothelial defence against ischemic damage Water / salt balance in TAL and DCT Mo et al, Kidney Int, 2004 Wiggins et al, Clin Chim Acta, 1987 El-Achkar et al, JASN, 2008

8 Uromodulin Related Diseases

9

10 ALLELISM of MCKD, FJHN and GCKD MCKD - Dominant tubulo-interstitial nephritis - Hypostenuria, ESRD, Medullary cysts - Hyperuricemia and gout FJHN - Phenotypic similarity with MCKD (no medullary cysts) - Tubulo Interstitial Nephropathy, - Hyperuricemia and gout GCKD - Glomerular cysts: dilatation of Bowmans space - Sporadic or dominant disorder - Also part of metabolic syndrome (MODY5; HNF-1beta mut.)

11 Summary of UMOD published mutations 43 mutations 26 Cys-affecting 1 Gly to Cys 13 other missense 3 in frame deletions Exon 4 Exon 5 98% mutations (42/43)

12 GCKD MCKD/FJHN

13 NormalMCKD

14 GCKD

15 MCKD/FJHN kidney biopsy Dr. Vivette DAgati, Dept of Pathology, Columbia Univ

16 Urinary uromodulin is reduced in MCKD2/FJHN patients MCKD#1 Uromodulin urinary excretion in affected individuals: Amount of daily excreted uromodulin is 15 to 30 fold decreased (Bleyer et al., Kidney Int 2004) Excreted uromodulin is wild type only (Dahan et al., J Am Soc Nephrol, 2003)

17 MOLECULAR PATHOGENESIS In vitro studies

18 WT C148W Unpermeabilized HEK293 after transfection (6 hrs)

19 WTC150S Mutant uromodulin is retained in the ER

20 ANIMAL MODELS THP -/- Raffi et al Kidney In, Are more prone to develop urinary tract infection. - Do no develop MCKD -Knock-in mice ?

21 Mechanisms Urine concentration defect interaction with ROMK Hyperuricemia idem TI fibrosis ? Cyst formation ?

22 UAKD Uromodulin Associated Kidney Diseases - Chr 17q12(HNF1-beta) - Chr 1q21? - Chr 1q41?

23 Atypical familial juvenile hyperuricemic nephropathy associated with a HNF1B mutation Bingham el al, Kidney Int 2003

24 UMOD can be considered as direct transcriptional targets of HNF1B Gresh et al, EMBO J, 2004 Renal-specific inactivation of HNF1B

25 Hodanova et al Kidney Int 2005 UROMODULIN ASSOCIATED KIDNEY DISEASE ControlUmod Mutation Linkage 1q41 ?

26 CONCLUSIONS The re-discovery of an old actor such as Uromodilun offers the opportunity to open a new area of research on renal fibrosis that may lead to important advancements

27 Thank You!

28 MCKD/FJHN Italian Consortium University of Turin Mario De Marchi Antonio Amoroso Molecular analysis G. Gaslini Institute, Genoa Gianluca Caridi Gian Marco Ghiggeri Clinical analysis Molecular analysis University of Brescia Francesco Scolari Clinical analysis Kidney pathology DTI, Dibit-HSR, Milan Luca Rampoldi Cellular and animal models Linkage analysis University of Padua Luisa Murer Kidney pathology


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