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Mapping and functional characterization of murine kidney injury molecule-1 proteolytic cleavage site

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Abstract

Kidney injury molecule-1 (KIM-1), also known as T cell immunoglobulin and mucin domain 1 (TIM-1), is a transmembrane glycoprotein expressed on proximal tubule epithelia during acute kidney injury (AKI). Extracellular domain of KIM-1 undergoes spontaneous and activated ectodomain shedding into urine and blood via metalloproteases. Soluble KIM-1 (blood and urinary) is a reliable clinical biomarker of proximal tubular injury, but the biological significance of shedding remains unknown. The aim of this study was to identify the specific shedding enzyme and the proteolytic cleavage site of murine KIM-1, followed by the characterization of its functional relevance. In this regard, isoleucine (I) I202 was identified as the potential cleavage site. Mutation of isoleucine I202 to glutamine (I202Q) or alanine (I202A) significantly reduced both constitutive and induced KIM-1 shedding and ultimately efferocytosis. It was also uncovered that ADAM10 is the major sheddase that mediates the proteolytic cleavage of murine KIM-1. In addition, ADAM10-induced KIM-1 shedding was required for efficient phagocytic clearance of apoptotic cells. Importantly, the findings that the addition of exogenous shed KIM-1 rescued the phagocytic impairment suggest that shed KIM-1 is capable of modulating efferocytosis of apoptotic bodies and could represent a potential functional role of the soluble ectodomain KIM-1 during AKI.

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Data Availability Statement

Data that support the findings of this study are available from the corresponding author upon request.

References

  1. van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA (2007) Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol 212:209–217. https://doi.org/10.1002/path.2175

    Article  CAS  PubMed  Google Scholar 

  2. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M (1998) Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 273:4135–4142. https://doi.org/10.1074/jbc.273.7.4135

    Article  CAS  PubMed  Google Scholar 

  3. Han WK, Alinani A, Wu C-L, Michaelson D, Loda M, McGovern FJ, Thadhani R, Bonventre JV (2005) Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma. J Am Soc Nephrol 16:1126–1134. https://doi.org/10.1681/asn.2004070530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. van Timmeren MM, Bakker SJ, Vaidya VS, Bailly V, Schuurs TA, Damman J, Stegeman CA, Bonventre JV, van Goor H (2006) Tubular kidney injury molecule-1 in protein-overload nephropathy. Am J Physiol Renal Physiol 291:F456–F464. https://doi.org/10.1152/ajprenal.00403.2005

    Article  CAS  PubMed  Google Scholar 

  5. Kuehn EW, Park KM, Somlo S, Bonventre JV (2002) Kidney injury molecule-1 expression in murine polycystic kidney disease. Am J Physiol Renal Physiol 283:F1326–F1336. https://doi.org/10.1152/ajprenal.00166.2002

    Article  CAS  PubMed  Google Scholar 

  6. Sabbisetti VS, Waikar SS, Antoine DJ, Smiles A, Wang C, Ravisankar A, Ito K, Sharma S, Ramadesikan S, Lee M, Briskin R, De Jager PL, Ngo TT, Radlinski M, Dear JW, Park KB, Betensky R, Krolewski AS, Bonventre JV (2014) Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J Am Soc Nephrol 25:2177–2186. https://doi.org/10.1681/asn.2013070758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nowak N, Skupien J, Niewczas MA, Yamanouchi M, Major M, Croall S, Smiles A, Warram JH, Bonventre JV, Krolewski AS (2016) Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes. Kidney Int 89:459–467. https://doi.org/10.1038/ki.2015.314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV (2008) Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest 118:1657–1668. https://doi.org/10.1172/jci34487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY, Hsiao LL, Ichimura T, Kuchroo V, Bonventre JV (2015) KIM-1-mediated phagocytosis reduces acute injury to the kidney. J Clin Invest 125:1620–1636. https://doi.org/10.1172/JCI75417

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ismail OZ, Zhang X, Bonventre JV, Gunaratnam L (2016) G protein alpha12 (Galpha12) is a negative regulator of kidney injury molecule-1-mediated efferocytosis. Am J Physiol Renal Physiol 310:F607–f620. https://doi.org/10.1152/ajprenal.00169.2015

    Article  CAS  PubMed  Google Scholar 

  11. Arai S, Kitada K, Yamazaki T, Takai R, Zhang X, Tsugawa Y, Sugisawa R, Matsumoto A, Mori M, Yoshihara Y, Doi K, Maehara N, Kusunoki S, Takahata A, Noiri E, Suzuki Y, Yahagi N, Nishiyama A, Gunaratnam L, Takano T, Miyazaki T (2016) Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice. Nat Med 22:183–193. https://doi.org/10.1038/nm.4012

    Article  CAS  PubMed  Google Scholar 

  12. Yamazaki T, Sugisawa R, Hiramoto E, Takai R, Matsumoto A, Senda Y, Nakashima K, Nelson PS, Lucas JM, Morgan A, Li Z, Yamamura KI, Arai S, Miyazaki T (2016) A proteolytic modification of AIM promotes its renal excretion. Sci Rep 6:38762. https://doi.org/10.1038/srep38762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K (2009) Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113:3821–3830. https://doi.org/10.1182/blood-2008-10-185884

    Article  CAS  PubMed  Google Scholar 

  14. Savill J, Dransfield I, Gregory C, Haslett C (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965–975. https://doi.org/10.1038/nri957

    Article  CAS  PubMed  Google Scholar 

  15. Umetsu SE, Lee WL, McIntire JJ, Downey L, Sanjanwala B, Akbari O, Berry GJ, Nagumo H, Freeman GJ, Umetsu DT, DeKruyff RH (2005) TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nat Immunol 6:447–454. https://doi.org/10.1038/ni1186

    Article  CAS  PubMed  Google Scholar 

  16. Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre JV (2002) Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem 277:39739–39748. https://doi.org/10.1074/jbc.M200562200

    Article  CAS  PubMed  Google Scholar 

  17. Caescu CI, Jeschke GR, Turk BE (2009) Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. Biochem J 424:79–88. https://doi.org/10.1042/BJ20090549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang Z, Humphreys BD, Bonventre JV (2007) Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region. J Am Soc Nephrol 18:2704–2714. https://doi.org/10.1681/asn.2007030325

    Article  CAS  PubMed  Google Scholar 

  19. Coca SG, Garg AX, Thiessen-Philbrook H, Koyner JL, Patel UD, Krumholz HM, Shlipak MG, Parikh CR, Consortium T-A (2014) Urinary biomarkers of AKI and mortality 3 years after cardiac surgery. J Am Soc Nephrol 25:1063–1071. https://doi.org/10.1681/ASN.2013070742

    Article  PubMed  Google Scholar 

  20. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (2002) Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62:237–244. https://doi.org/10.1046/j.1523-1755.2002.00433.x

    Article  CAS  PubMed  Google Scholar 

  21. Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, Muniappa N, Thudium D, Gerhold D, Holder DJ, Bobadilla NA, Marrer E, Perentes E, Cordier A, Vonderscher J, Maurer G, Goering PL, Sistare FD, Bonventre JV (2010) Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol 28:478–485. https://doi.org/10.1038/nbt.1623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gandhi R, Yi J, Ha J, Shi H, Ismail O, Nathoo S, Bonventre JV, Zhang X, Gunaratnam L (2014) Accelerated receptor shedding inhibits kidney injury molecule-1 (KIM-1)-mediated efferocytosis. Am J Physiol Renal Physiol 307:F205–F221. https://doi.org/10.1152/ajprenal.00638.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schweigert O, Dewitz C, Moller-Hackbarth K, Trad A, Garbers C, Rose-John S, Scheller J (2014) Soluble T cell immunoglobulin and mucin domain (TIM)-1 and -4 generated by A Disintegrin And Metalloprotease (ADAM)-10 and -17 bind to phosphatidylserine. Biochim Biophys Acta 1843:275–287. https://doi.org/10.1016/j.bbamcr.2013.11.014

    Article  CAS  PubMed  Google Scholar 

  24. Guo L, Takino T, Endo Y, Domoto T, Sato H (2012) Shedding of kidney injury molecule-1 by membrane-type 1 matrix metalloproteinase. J Biochem 152:425–432. https://doi.org/10.1093/jb/mvs082

    Article  CAS  PubMed  Google Scholar 

  25. Lim AI, Chan LY, Lai KN, Tang SC, Chow CW, Lam MF, Leung JC (2012) Distinct role of matrix metalloproteinase-3 in kidney injury molecule-1 shedding by kidney proximal tubular epithelial cells. Int J Biochem Cell Biol 44:1040–1050. https://doi.org/10.1016/j.biocel.2012.03.015

    Article  CAS  PubMed  Google Scholar 

  26. Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV (2004) Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol 286:F552–F563. https://doi.org/10.1152/ajprenal.00285.2002

    Article  CAS  PubMed  Google Scholar 

  27. Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR (2009) Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 53:961–973. https://doi.org/10.1053/j.ajkd.2008.11.034

    Article  PubMed  PubMed Central  Google Scholar 

  28. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, Jaber BL, Acute Kidney Injury Advisory Group of the American Society of N (2013) World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 8:1482–1493. https://doi.org/10.2215/CJN.00710113

    Article  PubMed  PubMed Central  Google Scholar 

  29. Waikar SS, Liu KD, Chertow GM (2008) Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol 3:844–861. https://doi.org/10.2215/CJN.05191107

    Article  PubMed  Google Scholar 

  30. Ympa YP, Sakr Y, Reinhart K, Vincent JL (2005) Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med 118:827–832. https://doi.org/10.1016/j.amjmed.2005.01.069

    Article  PubMed  Google Scholar 

  31. Wald R, Quinn RR, Luo J, Li P, Scales DC, Mamdani MM, Ray JG (2009) Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. Jama 302:1179–1185. https://doi.org/10.1001/jama.2009.1322

    Article  CAS  PubMed  Google Scholar 

  32. James MT, Pannu N, Hemmelgarn BR, Austin PC, Tan Z, McArthur E, Manns BJ, Tonelli M, Wald R, Quinn RR, Ravani P, Garg AX (2017) Derivation and external validation of prediction models for advanced chronic kidney disease following acute kidney injury. JAMA 318:1787–1797. https://doi.org/10.1001/jama.2017.16326

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang ZX, Shek K, Wang S, Huang X, Lau A, Yin Z, Sun H, Liu W, Garcia B, Rittling S, Jevnikar AM (2010) Osteopontin expressed in tubular epithelial cells regulates NK cell-mediated kidney ischemia reperfusion injury. J Immunol 185:967–973. https://doi.org/10.4049/jimmunol.0903245

    Article  CAS  PubMed  Google Scholar 

  34. Ismail OZ, Zhang X, Wei J, Haig A, Denker BM, Suri RS, Sener A, Gunaratnam L (2015) Kidney injury molecule-1 protects against Galpha12 activation and tissue damage in renal ischemia-reperfusion injury. Am J Pathol 185:1207–1215. https://doi.org/10.1016/j.ajpath.2015.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee JY, Ismail OZ, Zhang X, Haig A, Lian D, Gunaratnam L (2018) Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation. Am J Transplant 18:2021–2028. https://doi.org/10.1111/ajt.14745

    Article  CAS  PubMed  Google Scholar 

  36. Humphreys BD, Xu F, Sabbisetti V, Grgic I, Movahedi Naini S, Wang N, Chen G, Xiao S, Patel D, Henderson JM, Ichimura T, Mou S, Soeung S, McMahon AP, Kuchroo VK, Bonventre JV (2013) Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 123:4023–4035. https://doi.org/10.1172/JCI45361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Thorp E, Vaisar T, Subramanian M, Mautner L, Blobel C, Tabas I (2011) Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cdelta, and p38 mitogen-activated protein kinase (MAPK). J Biol Chem 286:33335–33344. https://doi.org/10.1074/jbc.M111.263020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Horiuchi K, Le Gall S, Schulte M, Yamaguchi T, Reiss K, Murphy G, Toyama Y, Hartmann D, Saftig P, Blobel CP (2007) Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. Mol Biol Cell 18:176–188. https://doi.org/10.1091/mbc.e06-01-0014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Driscoll WS, Vaisar T, Tang J, Wilson CL, Raines EW (2013) Macrophage ADAM17 deficiency augments CD36-dependent apoptotic cell uptake and the linked anti-inflammatory phenotype. Circ Res 113:52–61. https://doi.org/10.1161/CIRCRESAHA.112.300683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sizing ID, Bailly V, McCoon P, Chang W, Rao S, Pablo L, Rennard R, Walsh M, Li Z, Zafari M, Dobles M, Tarilonte L, Miklasz S, Majeau G, Godbout K, Scott ML, Rennert PD (2007) Epitope-dependent effect of anti-murine TIM-1 monoclonal antibodies on T cell activity and lung immune responses. J Immunol 178:2249–2261. https://doi.org/10.4049/jimmunol.178.4.2249

    Article  CAS  PubMed  Google Scholar 

  41. Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Asp Med 29:258–289. https://doi.org/10.1016/j.mam.2008.08.001

    Article  CAS  Google Scholar 

  42. Kato T, Hagiyama M, Ito A (2018) Renal ADAM10 and 17: their physiological and medical meanings. Front Cell Dev Biol 6:153–153. https://doi.org/10.3389/fcell.2018.00153

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ludwig A, Hundhausen C, Lambert MH, Broadway N, Andrews RC, Bickett DM, Leesnitzer MA, Becherer JD (2005) Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 8:161–171. https://doi.org/10.2174/1386207053258488

    Article  CAS  PubMed  Google Scholar 

  44. Hoettecke N, Ludwig A, Foro S, Schmidt B (2010) Improved synthesis of ADAM10 inhibitor GI254023X. Neurodegener Dis 7:232–238. https://doi.org/10.1159/000267865

    Article  CAS  PubMed  Google Scholar 

  45. Herzog C, Haun RS, Ludwig A, Shah SV, Kaushal GP (2014) ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A. J Biol Chem 289:13308–13322. https://doi.org/10.1074/jbc.M114.559088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C (2017) An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med 9:1356–1365. https://doi.org/10.15252/emmm.201707672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Meyers JH, Chakravarti S, Schlesinger D, Illes Z, Waldner H, Umetsu SE, Kenny J, Zheng XX, Umetsu DT, DeKruyff RH, Strom TB, Kuchroo VK (2005) TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation. Nat Immunol 6:455–464. https://doi.org/10.1038/ni1185

    Article  CAS  PubMed  Google Scholar 

  48. Angiari S, Donnarumma T, Rossi B, Dusi S, Pietronigro E, Zenaro E, Della Bianca V, Toffali L, Piacentino G, Budui S, Rennert P, Xiao S, Laudanna C, Casasnovas JM, Kuchroo VK, Constantin G (2014) TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity 40:542–553. https://doi.org/10.1016/j.immuni.2014.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Santiago C, Ballesteros A, Martinez-Munoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM (2007) Structures of T cell immunoglobulin mucin protein 4 show a metal-ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27:941–951. https://doi.org/10.1016/j.immuni.2007.11.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Dr. Xizhong Zhang and Bradly Shrum for providing their technical expertise.

Funding

This work was supported by funds from the Canadian Institutes of Health Research (HDK 378121), the Kidney Foundation of Canada (KFOC160007), and Division of Nephrology at Western University.

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Author notes

  1. Saranga Sriranganathan and Elena Tutunea-Fatan have contributed equally to this work.

Authors and Affiliations

  1. Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London Health Sciences Centre, London, ON, Canada

    Saranga Sriranganathan, Elena Tutunea-Fatan, Alina Abbasi & Lakshman Gunaratnam

  2. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Saranga Sriranganathan & Lakshman Gunaratnam

  3. Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, 339 Windermere Road, Room A10-208, London, ON, N6A 5A5, Canada

    Lakshman Gunaratnam

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  1. Saranga Sriranganathan
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SS contributed to data collection, analysis, and manuscript preparation. ETF contributed to data collection, analysis, manuscript preparation, and editing. AA contributed to study design. LG contributed to study conception, interpretation of data, and editing the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lakshman Gunaratnam.

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Sriranganathan, S., Tutunea-Fatan, E., Abbasi, A. et al. Mapping and functional characterization of murine kidney injury molecule-1 proteolytic cleavage site. Mol Cell Biochem 476, 1093–1108 (2021). https://doi.org/10.1007/s11010-020-03975-5

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