Renal Immunopathology (David J. Salant, MD)
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). Three postdoctoral fellows are involved in the following projects:
- 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 role of anti-PLA2R in the development of recurrent membranous nephropathy post renal transplantation.
- 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.
- We are also engaged in studies to elucidate the role of Notch signaling in kidney development and in immune-mediated kidney injury using conditional knockouts.
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
- 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.
- 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.
- 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.
- 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.
- Cybulsky AV, Quigg RJ and Salant DJ. Experimental Membranous Nephropathy Redux (invited review). Am J Physiol Renal Physiol 2005 (In press).
- Sumi E, Iehara N, Akiyama H, Matsubara T, Mima A, Kanamori H, Fukatsu A, Salant DJ, Kita T, Arai H, Doi T: SRY-Related HMG Box 9 Regulates the Expression of Col4a2 through Transactivating Its Enhancer Element in Mesangial Cells. Am J Pathol, 17: 1854-1864, 2007.
- Imai N, Hishikawa K, Marumo T, Hirahashi J, Inowa T, Matsuzaki Y, Okano H, Kitamura T, Salant DJ, and Fujita T. Inhibition of histone deacetylase activates side population cells in kidney and partially reverses chronic renal injury. Stem Cells 25: 2469-2475, 2007.
- 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.
- Beck LH, Salant DJ. Causes and diagnosis of membranous nephropathy. UpToDate 17.1, 2007.
- 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.
- 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.
- Kopel T, Salant DJ. Dense deposit disease (membranoproliferative glomerulonephritis type II). UpToDate 17.1, 2009.
- 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.