Journal Article

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

Masayuki Iyoda, Kelly L. Hudkins, Tomasz A. Wietecha, Miriam C. Banas, Shunhua Guo, Gang Liu, Li Wang, Jolanta Kowalewska and Charles E. Alpers

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 22, issue 12, pages 3451-3461
Published in print December 2007 | ISSN: 0931-0509
Published online August 2007 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfm502
All-trans-retinoic acid aggravates cryoglobulin-associated membranoproliferative glomerulonephritis in mice

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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, α-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)

Journal Article.  5935 words.  Illustrated.

Subjects: Nephrology

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