A Dexamethasone Prodrug Reduces the Renal Macrophage Response and Provides Enhanced Resolution of Established Murine Lupus Nephritis

Fang, Yuan; Tabor, Dana E.; Nelson, Richard Κ.; Yuan, Hongjiang; Zhang, Yijia; Nuxoll, Jenny; Bynoté, Kimberly K.; Lele, Subodh M.; Wang, Dong; Gould, Karen A.

doi:10.1371/journal.pone.0081483

Cited by 16 publications

(27 citation statements)

References 30 publications

(41 reference statements)

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“…This is in general agreement with reports in the literature of the median survival of saline-treated NZB/W F1 female mice (∼35 weeks). 19−22 In comparison, two out of 11 mice treated with Dex died, and all ZSJ-0228-treated mice survived. The apparent trend of the ZSJ-0228 group toward better survival rates than the Dex group did not reach statistical significance ( P = 0.17).…”

Section: Resultsmentioning

confidence: 96%

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

et al. 2018

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Nephritis is one of the major complications of systemic lupus erythematosus. While glucocorticoids (GCs) are frequently used as the first-line treatment for lupus nephritis (LN), long-term GC usage is often complicated by severe adverse effects. To address this challenge, we have developed a polyethylene glycol-based macromolecular prodrug (ZSJ-0228) of dexamethasone, which self-assembles into micelles in aqueous media. When compared to the dose equivalent daily dexamethasone 21-phosphate disodium (Dex) treatment, monthly intravenous administration of ZSJ-0228 for two months significantly improved the survival of lupus-prone NZB/W F1 mice and was much more effective in normalizing proteinuria, with clear histological evidence of nephritis resolution. Different from the dose equivalent daily Dex treatment, monthly ZSJ-0228 administration has no impact on the serum anti-double-stranded DNA (anti-dsDNA) antibody level but can significantly reduce renal immune complex deposition. No significant systemic toxicities of GCs (e.g., total IgG reduction, adrenal gland atrophy, and osteopenia) were found to be associated with ZSJ-0228 treatment. In vivo imaging and flow cytometry studies revealed that the fluorescent-labeled ZSJ-0228 primarily distributed to the inflamed kidney after systemic administration, with renal myeloid cells and proximal tubular epithelial cells mainly responsible for its kidney retention. Collectively, these data suggest that the ZSJ-0228’s potent local anti-inflammatory/immunosuppressive effects and improved safety may be attributed to its nephrotropicity and cellular sequestration at the inflamed kidney tissues. Pending further optimization, it may be developed into an effective and safe therapy for improved clinical management of LN.

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Section: Resultsmentioning

confidence: 96%

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

et al. 2018

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“…The guidelines mention that histological risk factors could be a good reason to combine RASB with glucocorticoids, although no trials have been performed [33]. Glucocorticoids reduce macrophage infiltration and tubulo-interstitial injury in murine lupus nephritis [34]. Thus, early combined treatment with RASB and glucocorticoids may improve the long-term prognosis in patients with pronounced macrophage interstitial infiltration.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of morphologic and morphometric analyses in IgA nephropathy biopsies

et al. 2016

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Background: IgA nephropathy (IgAN) exhibits a variable course ranging from a benign condition to progressive renal failure with a high proportion of patients undergoing end-stage renal disease in the long term. It is unclear how to predict the risk of this progression. Mesangial C4d deposition has been found to be associated with a poor prognosis. Our aim was to search histological lesions with possible prognostic value in IgAN biopsies performed at the time of the diagnosis. Methods: Clinical and laboratory records of 44 patients undergoing renal biopsy were reviewed. IgAN was diagnosed in 32 patients and minimal change disease (MCD) in 12. C4d deposition, glomerular endothelial cell area, glomerular and interstitial macrophages were evaluated in all biopsies. Clinical and laboratory data were available in all IgAN patients at the time of diagnosis and in 21 patients at the end of follow-up (mean follow-up 48.09 ± 19.69 months). Results: All IgAN and MCD biopsies were C4d negative. The number of glomerular macrophages and the area of glomerular endothelial cells in IgAN were greater than in MCD (P < 0.001 and P < 0.0001, respectively), indicating glomerular inflammation associated with endothelial cell enlargement. Glomerular macrophages positively correlated with diffuse IgA and fibrinogen immunoreactivity (P < 0.02 and P < 0.002, respectively). Interstitial macrophages positively correlated with segmental glomerulosclerosis (P < 0.01) and tubular atrophy (P < 0.001), according to the Oxford classification. They correlated with hypertension (P < 0.03) and renal functional impairment both at the time of biopsy and at the end of follow-up. The receiver operating characteristic analysis curve and a cut-off value of ≥19.5 macrophages per high power field showed 75.0% sensitivity and 88.9% specificity in predicting worse clinical outcome. A Poisson generalized regression fit model showed that hypertension and tubular atrophy were the most significant factors in predicting a high number of interstitial macrophages. Conclusions: The number of interstitial macrophages correlated with hypertension, histological damage, functional impairment at the time of biopsy and worse outcome. A high number of interstitial macrophages in C4d negative biopsies may allow the identification of patients at increased risk of progression to renal failure.

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“…Samples were assayed in duplicate for each ELISA. The anti-chromatin IgG and anti-dsDNA IgG concentrations were determined using plates prepared as described previously [8, 24]. Autoantibody levels in these samples were quantitated in arbitrary ELISA units (U/μl) based upon a standard curve generated by serial dilution of a positive control sample that was made by pooling serum from a group of (NZB × NZW)F1 females with heavy albuminuria.…”

Section: Methodsmentioning

confidence: 99%

Estrogen receptor alpha signaling promotes Sle1-induced loss of tolerance and immune cell activation and is responsible for sex bias in B6.Sle1 congenic mice

Yoachim

Nuxoll

Bynoté

et al. 2015

Clinical Immunology

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Sex bias in lupus incidence is thought to be due, in part, to the ability of estrogens to promote loss of tolerance. Previously, we showed that estrogens promote lupus via estrogen receptor α (ERα). C57BL/6 (B6) mice carrying the Sle1 lupus susceptibility locus (B6.Sle1) display loss of tolerance and develop anti-nuclear antibodies and immune cell hyperactivation. The incidence of loss of tolerance in B6.Sle1 females is greater than in males. Here, we show that a deficiency of either estrogens or ERα attenuates loss of tolerance and autoantibody development in B6.Sle1 females. Furthermore, we demonstrate that immune cell activation in B6.Sle1 mice shows sex bias and that ERα deficiency diminishes this phenotype in B6.Sle1 females. Thus, estrogens, acting via ERα, control sex bias in the Sle1 phenotype. Furthermore, we show that ERα may impact the Sle1 phenotype by modulating the expression Pbx1, one of genes that underlies the Sle1 locus.

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A Dexamethasone Prodrug Reduces the Renal Macrophage Response and Provides Enhanced Resolution of Established Murine Lupus Nephritis

Cited by 16 publications

References 30 publications

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

Prognostic value of morphologic and morphometric analyses in IgA nephropathy biopsies

Estrogen receptor alpha signaling promotes Sle1-induced loss of tolerance and immune cell activation and is responsible for sex bias in B6.Sle1 congenic mice

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