Renal Immunopathology (David J. Salant, MD)

Chief of Nephrology
Chief of Nephrology

Experimental models of immunological glomerular diseases and autoimmunity resembling those seen in man are used to obtain a fundamental understanding of the immunopathogenetic mechanisms of injury.

Antibody-mediated podocyte injury

The focus of Dr. Salant’s laboratory is on the immune basis of glomerular diseases with particular regard to the humoral mechanisms of glomerular cell injury. Current work will elucidate the mechanisms by which antibodies alter the function and morphology of glomerular visceral epithelial cells (podocytes). Postdoctoral fellows are involved in the following projects:

  1. We have identified the target antigen in human membranous nephropathy as the phospholipase A2 receptor (PLA2R) and shown that about 75% of patients have circulating ant-PLA2R autoantibodies. Current work is directed at defining the mechanisms of podocyte injury induced by anti-PLA2R using a combination of in vitro, in vivo and human genetic techniques. Additional studies will explore the immune basis of this organ-specific autoimmune disease.
  2. Ongoing interests include the role of podocyte-specific antibodies, and the effects of complement-mediated injury on podocyte structure, composition of the filtration slit diaphragm and its attachment to the cytoskeleton, and on cell-matrix adhesion using animal models, cell biological and immunochemical methodologies.

Mechanisms of post-inflammatory renal fibrogenesis

We have also developed a murine model of antibody-dependent rapidly progressive glomerulonephritis in which necrotizing and crescentic glomerulonephritis is associated with the activation of chemokine and interstitial-type collagen genes, followed by the development of interstitial fibrosis and renal failure. Since interstitial fibrosis and tubular atrophy are common to all forms of chronic progressive renal diseases and are the most reliable pathological indicators of an adverse long-term prognosis in humans, this mouse model in which the onset of immune injury is rapidly followed (within 5 days) by the induction and proliferation of interstitial cells expressing high levels of mRNA for type I collagen affords a unique opportunity to study the mechanisms of post-inflammatory renal fibrogenesis.

References

  1. Yuan H, Takeuchi E, Salant DJ. The podocyte slit-diaphragm protein nephrin is linked to the actin cytoskeleton. Am J Physiol Renal 282: F585– F591, 2002.
  2. Yuan H, Takeuchi E, Taylor GA, McLaughlin M, Brown D, Salant DJ. Nephrin dissociates from actin and its expression is reduced in early experimental membranous nephropathy. J Am Soc Nephrol 13:946-956, 2002.
  3. Saran, A.M., Yuan, H., Takeuchi, E., McLaughlin, M., and Salant DJ Complement mediates nephrin redistribution and actin dissociation in experimental membranous nephropathy. Kidney Int 64:2072-2078, 2003.
  4. Lin F, Salant DJ, Meyerson H, Morgan P, Medof ME. Respective roles of DAF and CD59 in circumventing glomerular injury in acute nephrotoxic serum nephritis. J Immunol 172: 2636-2642, 2004.
  5. Cybulsky AV, Quigg RJ and Salant DJ. Experimental Membranous Nephropathy Redux (invited review). Am J Physiol Renal Physiol 2005 (In press).
  6. Salant DJ, Sanchorawala V, D’Agati VD: CJASN Clinical Conference: A Case of Atypical Light Chain Deposition Disease—Diagnosis and Treatment. Clin J Am Soc Nephrol 2:858–867, 2007.
  7. Beck LH, Salant DJ. Causes and diagnosis of membranous nephropathy. UpToDate 17.1-19.1, 2007-2016.
  8. Pradere JP, Gonzalez J, Klein J, Valet P, Gres S, Salant D, Bascands JL, Saulnier-Blache JS, and Schanstra JP. Lysophosphatidic acid and renal fibrosis. Biochim Biophys Acta, 2008.
  9. Salant DJ, Patel PS. Polycystic Kidney Disease and Other Inherited Tubular Disorders. In, Harrison’s Principle of Internal Medicine (edited by Fauci AS, Kasper DL, Braunwald E, et al), 17th edition, McGraw-Hill, New York, 2008, p. 1797.
  10. Kopel T, Salant DJ. Dense deposit disease and C3 glomerulonephritis. UpToDate 17.1-19.1, 2009 – 2016.
  11. Beck, LH, Jr., Bonegio, RG, Lambeau, G, Beck, DM, Powell, DW, cummins, TD, Klein, JB Salant, DJ: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Eng J Med, 361:11-21,2009.
  12. Klein J, Gonzalez J, Decramer S, Bandin F, Neau E, Salant DJ, Heeringa P, Pesquero JB, Schanstra JP, Bascands JL: Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis. J Am Soc Nephrol, 21:1157-1164, 2010. PMCID: PMC3152233.
  13. Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, Muller CA, Kalluri R, Zeisberg M: Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med, 16: 544-550, 2010. PMCID: PMC3106179.
  14. Bonegio RG, Beck, LH, Kahlon RK, Lu W Salant DJ: The fate of Notch-deficient nephrogenic progenitor cells during metanephric kidney development. Kidney Int, 79: 1099-1112, 2011. PMID: 21270765, PMCID: PMC5033618.
  15. Hofstra JM, Beck, LH, Jr., Beck DM, Wetzels JF Salant DJ: Anti-Phospholipase A2 Receptor Antibodies Correlate with Clinical Status in Idiopathic Membranous Nephropathy. Clin J Am Soc Nephrol, 6: 1286-1291, 2011. PMID: 21474589, PMCID: 3109923.
  16. Qin W, Beck LH, Jr, Salant DJ, Zeng C, Chen Z, Liu Z. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol, 22:1137-1143, 2011. Published online before print May 12, 2011. PMID: 21566055, PMCID: PMC3103733.
  17. Bollée G, Flamant M, Schordan S, Fligny C, Rumpel E, Milon M, Schordan E, Sabaa N, Vandermeersch S, Galaup A, Rodenas A, Casal I, Sunnarborg SW, Salant DJ, Kopp JB, Threadgill DW, Quaggin SE, Dussaule J-C, Germain S, Mesnard L, Endlich K, Boucheix C, Belenfant X, Callard P, Endlich N, Tharaux PL. Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nat Med, 17:1242-1250, 2011 (Epub 09/29/2011). PMCID: PMC3198052.
  18. Beck LH, Jr, Fervenza FC, Beck DM, Bonegio RGB, Malik FA, Erickson SB, Cosio FG, Cattran DC, Salant DJ: Rituximab-Induced Depletion of Anti-PLA2R Autoantibodies Predicts Response in Membranous Nephropathy. J Am Soc Nephrol, 22:1543-1550, 2011. PMCID PMC3148709.
  19. George B, Verma R, Soofi AA, Garg P, Zhang J, Park TJ, Giardino L, Ryzhova L, Johnstone DB, Wong H, Nihalani D, Salant DJ, Hanks SK, Curran T, Rastaldi MP, Holzman LB. Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J Clin Invest 122:674-692, 2012. PMCID: PMC3266791.
  20. Fan X, Li Q, Pisarek-Horowitz A, Rasouly HM, Wang X, Bonegio RG, Wang H, McLaughlin M, Mangos S, Kalluri R, Holzman LB, Drummond IA, Brown D, Salant DJ, Lu W. Inhibitory Effects of Robo2 on Nephrin: A Crosstalk between Positive and Negative Signals Regulating Podocyte Structure. Cell Rep 2:52-61, 2012. PMID:22840396. PMCID: PMC3627357.
  21. Timmermans SA, Ayalon R, van Paassen P, Beck LH, Jr., van Rie H, Wirtz JJ, Verseput GH, Frenken LA, Salant DJ, Cohen Tervaert JW: Anti-phospholipase A2 receptor antibodies and malignancy in membranous nephropathy. Am J Kidney Dis 62: 1223-1225, 2013. PMCID pending.
  22. Dai Y, Gu L, Yuan W, Yu Q, Ni Z, Ross MJ, Kaufman L, Xiong H, Salant DJ, He JC, Chuang PY: Podocyte-specific deletion of signal transducer and activator of transcription 3 attenuates nephrotoxic serum-induced glomerulonephritis. Kidney Int 84:950-961, 2013. PMCID: PMC3797218
  23. Beck LH, Jr., Salant DJ: Membranous nephropathy: from models to man. J Clin Invest, 124: 2307-2314, 2014. PMCID: PMC 4089468.
  24. Salant DJ, Cattran DC: Membranous Nephropathy. In, Comprehensive Clinical Nephrology, 5th Edition (edited by Johnson RJ, Feehally J, Floege J). Elsevier, Philadelphia, 2014, p. 239.
  25. Tomas NM*, Beck LH*, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, Dolla G, Hoxha E, Helmchen U, Dabert-Gay AS, Debayle D, Merchant M, Klein J, Salant DJ, Stahl RA, Lambeau G. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 371(24):2277-2287, 2014. PMCID: PMC4278759
  26. Kattah, A, Ayalon, R, Beck, LH, Jr., Sethi, S, Sandor, DG, Cosio, FG, Gandhi, MJ, Lorenz, EC, Salant, DJ, Fervenza, FC: Anti-phospholipase A(2) receptor antibodies in recurrent membranous nephropathy. Am J Transplant 15: 1349-1359, 2015. PMCID: PMC4472303
  27. Verma R, Venkatareddy M, Kalinowski A, Patel SR, Salant DJ, Garg P. Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury. Mol Cell Biol. 2015; 36(4):596-614. PMCID: PMC4751697
  28. Haas ME, Levenson AE, Sun X, Liao WH, Rutkowski JM, de Ferranti SD, Schumacher VA, Scherer PE, Salant DJ, Biddinger SB. The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia. Circulation. 2016 Jul 5; 134(1):61-72. PMID: 27358438.
  29. Fan X, Yang H, Kumar S, Tumelty KE, Pisarek-Horowitz A, Rasouly HM, Sharma R, Chan S, Tyminski E, Shamashkin M, Belghasem M, Henderson JM, Coyle AJ, Salant DJ, Berasi SP, Lu W. SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion. JCI Insight. 2016;1(19):e86934. PMC5111509
  30. Francis J, Beck LH, Jr., Salant DJ: Membranous Nephropathy: A Journey from Bench to Bedside. Invited narrative review on occasion of Donald W. Seldin Award 2015. Am J Kidney Dis 68: 138-147, 2016. PMCID: PMC4921260.