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NDT Advance Access originally published online on August 8, 2007
Nephrology Dialysis Transplantation 2007 22(12):3451-3461; doi:10.1093/ndt/gfm502
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


All-trans-retinoic acid aggravates cryoglobulin-associated membranoproliferative glomerulonephritis in mice

Masayuki Iyoda1,2, Kelly L. Hudkins1, Tomasz A. Wietecha1, Miriam C. Banas3, Shunhua Guo1, Gang Liu1, Li Wang1, Jolanta Kowalewska1 and Charles E. Alpers1

1University of Washington, Department of Pathology, Seattle, WA, USA, 2Department of Nephrology, Showa University School of Medicine, Tokyo, Japan and 3Department of Nephrology, University of Regensburg, Germany

Correspondence to: Charles E. Alpers, MD, University of Washington, Department of Pathology, 1959 NE Pacific Avenue Box 357470, Seattle, WA 98195, USA, Email: calp{at}u.washington.edu



  Abstract

Background. Transgenic (tg) mice overexpressing thymic stromal lymphopoietin (TSLP) develop mixed cryoglobulinaemia with renal disease closely resembling human cryoglobulinaemic membranoproliferative glomerulonephritis (MPGN), as well as systemic inflammation involving lung, liver and skin as a result of cryoglobulin deposits. We assessed the effect of all-trans-retinoic acid (ATRA), a powerful anti-inflammatory agent, on this model of cryoglobulinaemic MPGN.

Methods. Groups of male TSLP tg mice and wild-type controls were treated with either ATRA (20 mg/kg) or vehicle 3 times weekly by intraperitoneal injection for 4 or 8 weeks, when mice were then sacrificed. Routine histology and immunohistochemistry for collagen IV, {alpha}-smooth muscle actin, Mac-2 and Ki67 were performed. Immunoglobulin levels were measured by enzyme-linked immunosorbent assay.

Results. ATRA unexpectedly exacerbated renal injury in TSLP tg mice with increased glomerular extracellular matrix, mesangial cell activation, glomerular cell proliferation, glomerular macrophage influx and immune complex deposition. Systemic injuries involving liver and lung, and the amount of circulating cryoglobulins were all worsened by ATRA treatment. Furthermore, ATRA resulted in increased IgG1 and IgM levels, the main components of the cryoglobulins in TSLP tg mice, and a manifestation of an enhanced Th2 immune response.

Conclusions. ATRA is not protective but instead aggravates cryoglobulinaemic MPGN and its systemic manifestations in TSLP tg mice. We speculate these findings may be due to augmented production of pathogenic immunoglobulins and/or an enhanced systemic Th2 response. Although disappointing, our results also suggest caution in the application of retinoid therapy to human disease based on the largely positive animal data reported to date.

Keywords: cryoglobulinaemia; membranoproliferative glomerulonephritis (MPGN); retinoic acid; thymic stromal lymphopoietin (TSLP)

Received for publication: 10. 2.07
Accepted in revised form: 3. 7.07


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