Open AccessDexamethasone prodrug treatment prevents nephritis in lupus‐prone (NZB × NZW)F1 mice without causing systemic side effects
Author(s) -
Yuan Fang,
Nelson Richard K.,
Tabor Dana E.,
Zhang Yijia,
Akhter Mohammed P.,
Gould Karen A.,
Wang Dong
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34667
Subject(s) - dexamethasone , medicine , endocrinology , lupus nephritis , inflammation , kidney , immune system , immunology , disease
Objective To evaluate the potentially improved therapeutic efficacy and safety of nephrotropic macromolecular prodrugs of glucocorticoids (GCs) for the treatment of lupus nephritis. Methods Lupus‐prone female (NZB × NZW)F1 mice received monthly injections of N ‐(2‐hydroxypropyl) methacrylamide copolymer–based dexamethasone prodrug (P‐Dex) or daily injections of dexamethasone phosphate sodium (Dex; overall dose equivalent to that of P‐Dex) for 2 months. During treatment, the mice were monitored for albuminuria, mean arterial pressure, and serum autoantibody levels. Nephritis, renal immune complex levels, and macrophage infiltration were evaluated histologically. Bone quality was analyzed using peripheral dual x‐ray absorptiometry and micro–computed tomography. The in vivo distribution of P‐Dex was investigated using optical imaging, immunohistochemistry, and fluorescence‐activated cell sorting (FACS). The antiinflammatory effect of P‐Dex was validated using lipopolysaccharide‐activated human proximal tubule epithelial (HK‐2) cells. Results Monthly P‐Dex injections completely abolished albuminuria in the (NZB × NZW)F1 mice; this approach was significantly more efficacious than daily Dex treatment. P‐Dex treatment did not reduce serum levels of anti–double‐stranded DNA antibodies or renal immune complexes but did decrease macrophage infiltration, which is a marker of chronic inflammation. Immunohistochemical and FACS analyses revealed that P‐Dex was primarily sequestered by proximal tubule epithelial cells, and that it could attenuate the inflammatory response in HK‐2 cell culture. In contrast to Dex treatment, P‐Dex treatment did not lead to any significant deterioration of bone quality or reduction in the level of total serum IgG. Conclusion Macromolecularization of GCs renders them nephrotropic. Protracted retention, subcellular processing, and activation of GC prodrugs by kidney cells would potentiate nephritis resolution, with a reduced risk of systemic toxicities.