Hepatitis C (HCV) is the most common blood-borne infection in the United States and is endemic in most areas of the world. We and others have previously shown that in humans, the principal renal manifestation of chronic hepatitis C infection is development of a membranoproliferative glomerulonephritis (MPGN) most often associated with cryoglobulinemia. Cryoglobulins are immunoglobulin proteins that reversibly precipitate in the cold, leading to systemic disease in humans. Overexpression of thymic stromal lymphopoietin (TSLP), a recently cloned cytokine that promotes B cell development, in transgenic mice leads to production of large amounts of circulating mixed cryoglobulins and a renal disease that closely resembles human MPGN. In this proposal, we seek support for studies that will define the role of the immunoglobulin binding Fc receptors (FcR) of leukocytes, major mediators of inflammation in immune complex deposition disease, in this model and the role of the PDGF family of growth factors that mediates glomerular mesangial cell proliferation. Having developed a reproducible model of cryoglobulinemia/MPGN, we seek to develop a major modification of the model in Specific Aim 1 that will allow better testing of therapeutic applications in glomerulonephritis by allowing us to regulate the exposure of the kidney to the initiating cryoglobulinemic stimulus. We will place the promoter regulating expression of the TSLP gene under the control of a tetracycline responsive regulatory element using recently established technologies.
Specific Aim 2 will address the hypothesis that activation of specific classes of leukocyte Fc receptors are required for the full development of MPGN. The functional role of Fc receptors will be tested using combined transgenic and knockout mice. Inbreeding of multiple Fc receptor deficient strains with TSLP mice will shed light on the role of inflammatory pathways mediated by these two receptors in this model. We will test specific therapeutic interventions (e.g., neutralizing antibodies for these receptors) to interrupt these inflammatory pathways for efficacy in treating glomerular injury.
In Specific Aim 3 we will test the efficacy of blocking the activity of the PDGF growth factor family in ameliorating disease.
Specific Aim 4 will examine the effects of these interventions on systemic cryoglobulinemia. It is anticipated that the findings will lead to better treatments for cryoglobulinemia and associated MPGN.
|Guo, Shunhua; Wietecha, Tomasz A; Hudkins, Kelly L et al. (2011) Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis. Kidney Int 80:946-958|
|Bao, Lihua; Haas, Mark; Pippin, Jeffrey et al. (2009) Focal and segmental glomerulosclerosis induced in mice lacking decay-accelerating factor in T cells. J Clin Invest 119:1264-74|
|Taneda, Sekiko; Hudkins, Kelly L; Muhlfeld, Anja S et al. (2008) Protease nexin-1, tPA, and PAI-1 are upregulated in cryoglobulinemic membranoproliferative glomerulonephritis. J Am Soc Nephrol 19:243-51|
|Iyoda, Masayuki; Hudkins, Kelly L; Wietecha, Tomasz A et al. (2007) All-trans-retinoic acid aggravates cryoglobulin-associated membranoproliferative glomerulonephritis in mice. Nephrol Dial Transplant 22:3451-61|
|Humblet-Baron, Stephanie; Sather, Blythe; Anover, Stephanie et al. (2007) Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest 117:407-18|
|Astrakhan, Alexander; Omori, Miyuki; Nguyen, Thuc et al. (2007) Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development. Nat Immunol 8:522-31|
|Banas, Miriam C; Parks, W Tony; Hudkins, Kelly L et al. (2007) Localization of TGF-beta signaling intermediates Smad2, 3, 4, and 7 in developing and mature human and mouse kidney. J Histochem Cytochem 55:275-85|
|Smith, Kelly D; Alpers, Charles E (2005) Pathogenic mechanisms in membranoproliferative glomerulonephritis. Curr Opin Nephrol Hypertens 14:396-403|