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A dexamethasone prodrug reduces the renal macrophage response and provides enhanced resolution of established murine lupus nephritis.

Yuan F, Tabor DE, Nelson RK, Yuan H, Zhang Y, Nuxoll J, Bynoté KK, Lele SM, Wang D, Gould KA - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.

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.

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Impact of treatment on hypertension, splenomegaly and vasculitis in (NZB × NZW)F1 mice.(A), Mean arterial pressure was measured at pretreatment, 4-week, 8-week, 12 week time points via tail-cuff method. For the saline group, measurements were obtained only for the subset of mice surviving at each time point: 12 mice at 4-week time point; 11 mice at 8-week time point; 9 mice at 12-week time point (B), Spleen mass was determined at the time of sacrifice in each mouse. (C), A representative hematoxylin and eosin stained histological section illustrating a splenic vessel from each treatment group is provided. The arrow indicates perivascular fibrin deposits indicative of vasculitis. Scale bars: 50 μm; the asterisk (*) indicates a statistically significant difference (P < 0.05) from the saline control group. The double asterisk (**) indicates a statistically significant difference (P < 0.05) from the Dex group. The dagger (†) indicates a statistically significant difference (P < 0.05) from the pretreatment time point of the same treatment group. For saline and Dex treatments, n=13; for P-Dex treatment, n=9.
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pone-0081483-g005: Impact of treatment on hypertension, splenomegaly and vasculitis in (NZB × NZW)F1 mice.(A), Mean arterial pressure was measured at pretreatment, 4-week, 8-week, 12 week time points via tail-cuff method. For the saline group, measurements were obtained only for the subset of mice surviving at each time point: 12 mice at 4-week time point; 11 mice at 8-week time point; 9 mice at 12-week time point (B), Spleen mass was determined at the time of sacrifice in each mouse. (C), A representative hematoxylin and eosin stained histological section illustrating a splenic vessel from each treatment group is provided. The arrow indicates perivascular fibrin deposits indicative of vasculitis. Scale bars: 50 μm; the asterisk (*) indicates a statistically significant difference (P < 0.05) from the saline control group. The double asterisk (**) indicates a statistically significant difference (P < 0.05) from the Dex group. The dagger (†) indicates a statistically significant difference (P < 0.05) from the pretreatment time point of the same treatment group. For saline and Dex treatments, n=13; for P-Dex treatment, n=9.

Mentions: Since systemic inflammation and renal dysfunction promote hypertension in lupus patients and (NZB × NZW)F1 mice [21,22], we assessed the impact of treatment on mean arterial pressure (MAP). Prior to treatment, mice in the saline group were normotensive (Figure 4A). However, over the experimental time course, MAP rose significantly and virtually all of the mice in this group became hypertensive (Figure 5A; P ≤ 0.01). By contrast, there was no significant change in MAP in either the Dex or P-Dex groups over this time course (Figure 5A; P > 0.05).


A dexamethasone prodrug reduces the renal macrophage response and provides enhanced resolution of established murine lupus nephritis.

Yuan F, Tabor DE, Nelson RK, Yuan H, Zhang Y, Nuxoll J, Bynoté KK, Lele SM, Wang D, Gould KA - PLoS ONE (2013)

Impact of treatment on hypertension, splenomegaly and vasculitis in (NZB × NZW)F1 mice.(A), Mean arterial pressure was measured at pretreatment, 4-week, 8-week, 12 week time points via tail-cuff method. For the saline group, measurements were obtained only for the subset of mice surviving at each time point: 12 mice at 4-week time point; 11 mice at 8-week time point; 9 mice at 12-week time point (B), Spleen mass was determined at the time of sacrifice in each mouse. (C), A representative hematoxylin and eosin stained histological section illustrating a splenic vessel from each treatment group is provided. The arrow indicates perivascular fibrin deposits indicative of vasculitis. Scale bars: 50 μm; the asterisk (*) indicates a statistically significant difference (P < 0.05) from the saline control group. The double asterisk (**) indicates a statistically significant difference (P < 0.05) from the Dex group. The dagger (†) indicates a statistically significant difference (P < 0.05) from the pretreatment time point of the same treatment group. For saline and Dex treatments, n=13; for P-Dex treatment, n=9.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842961&req=5

pone-0081483-g005: Impact of treatment on hypertension, splenomegaly and vasculitis in (NZB × NZW)F1 mice.(A), Mean arterial pressure was measured at pretreatment, 4-week, 8-week, 12 week time points via tail-cuff method. For the saline group, measurements were obtained only for the subset of mice surviving at each time point: 12 mice at 4-week time point; 11 mice at 8-week time point; 9 mice at 12-week time point (B), Spleen mass was determined at the time of sacrifice in each mouse. (C), A representative hematoxylin and eosin stained histological section illustrating a splenic vessel from each treatment group is provided. The arrow indicates perivascular fibrin deposits indicative of vasculitis. Scale bars: 50 μm; the asterisk (*) indicates a statistically significant difference (P < 0.05) from the saline control group. The double asterisk (**) indicates a statistically significant difference (P < 0.05) from the Dex group. The dagger (†) indicates a statistically significant difference (P < 0.05) from the pretreatment time point of the same treatment group. For saline and Dex treatments, n=13; for P-Dex treatment, n=9.
Mentions: Since systemic inflammation and renal dysfunction promote hypertension in lupus patients and (NZB × NZW)F1 mice [21,22], we assessed the impact of treatment on mean arterial pressure (MAP). Prior to treatment, mice in the saline group were normotensive (Figure 4A). However, over the experimental time course, MAP rose significantly and virtually all of the mice in this group became hypertensive (Figure 5A; P ≤ 0.01). By contrast, there was no significant change in MAP in either the Dex or P-Dex groups over this time course (Figure 5A; P > 0.05).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.

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.

Show MeSH
Related in: MedlinePlus