title: A dexamethasone prodrug reduces the renal macrophage response and provides enhanced resolution of established murine lupus nephritis.
abstract: We evaluated the ability of a macromolecular prodrug of dexamethasone (P-Dex) to treat lupus nephritis in (NZB × NZW)F1 mice. We also explored the mechanism underlying the anti-inflammatory effects of this prodrug. P-Dex eliminated albuminuria in most (NZB × NZW)F1 mice. Furthermore, P-Dex reduced the incidence of severe nephritis and extended lifespan in these mice. P-Dex treatment also prevented the development of lupus-associated hypertension and vasculitis. Although P-Dex did not reduce serum levels of anti-dsDNA antibodies or glomerular immune complexes, P-Dex reduced macrophage recruitment to the kidney and attenuated tubulointerstitial injury. In contrast to what was observed with free dexamethasone, P-Dex did not induce any deterioration of bone quality. However, P-Dex did lead to reduced peripheral white blood cell counts and adrenal gland atrophy. These results suggest that P-Dex is more effective and less toxic than free dexamethasone for the treatment of lupus nephritis in (NZB × NZW)F1 mice. Furthermore, the data suggest that P-Dex may treat nephritis by attenuating the renal inflammatory response to immune complexes, leading to decreased immune cell infiltration and diminished renal inflammation and injury.
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors: Fang
authors: F
authors: Yuan
authors: Dana E
authors: DE
authors: Tabor
authors: Richard K
authors: RK
authors: Nelson
authors: Hongjiang
authors: H
authors: Yuan
authors: Yijia
authors: Y
authors: Zhang
authors: Jenny
authors: J
authors: Nuxoll
authors: Kimberly K
authors: KK
authors: Bynoté
authors: Subodh M
authors: SM
authors: Lele
authors: Dong
authors: D
authors: Wang
authors: Karen A
authors: KA
authors: Gould
mesh_terms: D000419:Albuminuria / Q000150:complications; D000818:Animals; D003907:Dexamethasone / Q000378:metabolism*; D004195:Disease Models, Animal; D006973:Hypertension / Q000150:complications; D007668:Kidney / Q000187:drug effects* / Q000276:immunology; D008181:Lupus Nephritis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D009395:Nephritis, Interstitial / Q000150:complications; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013163:Splenomegaly / Q000150:complications; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D011355:Prodrugs; D003907:Dexamethasone