Dexamethasone prodrug treatment prevents nephritis in lupus-prone (NZB × NZW)F1 mice without causing systemic side effects

Fang Yuan, Richard K. Nelson, Dana E. Tabor, Yijia Zhang, Mohammed P. Akhter, Karen A. Gould, Dong Wang

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)4029-4039
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number12
DOIs
StatePublished - Dec 2012

Fingerprint

Lupus Nephritis
Prodrugs
Dexamethasone
Glucocorticoids
Albuminuria
dexamethasone 21-phosphate
Nephritis
Antigen-Antibody Complex
Kidney
Therapeutics
Injections
Flow Cytometry
Serum
Macrophages
Bone and Bones
Optical Imaging
Autoantibodies
Lipopolysaccharides
Arterial Pressure
Anti-Inflammatory Agents

All Science Journal Classification (ASJC) codes

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Dexamethasone prodrug treatment prevents nephritis in lupus-prone (NZB × NZW)F1 mice without causing systemic side effects. / Yuan, Fang; Nelson, Richard K.; Tabor, Dana E.; Zhang, Yijia; Akhter, Mohammed P.; Gould, Karen A.; Wang, Dong.

In: Arthritis and Rheumatism, Vol. 64, No. 12, 12.2012, p. 4029-4039.

Research output: Contribution to journalArticle

Yuan, Fang ; Nelson, Richard K. ; Tabor, Dana E. ; Zhang, Yijia ; Akhter, Mohammed P. ; Gould, Karen A. ; Wang, Dong. / Dexamethasone prodrug treatment prevents nephritis in lupus-prone (NZB × NZW)F1 mice without causing systemic side effects. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 12. pp. 4029-4039.
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abstract = "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.",
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AB - 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.

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