Role of p300 in the Pathogenesis of Henoch-Schonlein Purpura Nephritis and as a New Target of Glucocorticoid Therapy in Mice
Henoch-Schonlein purpura (HSP) is a chronic, progressive, aseptic, multi-systemic vasculitis that primarily affects children aged 2 to 8 years. The disease is characterized by diffuse vasculitis accompanied by immunoglobulin A (IgA) deposition in various systems, including the skin, joints, kidneys, and gastrointestinal tract. In approximately 80% to 100% of cases, the kidneys are affected, leading to Henoch-Schonlein purpura nephritis (HSPN). HSPN is the second most common kidney disease in children, following acute nephritis and nephritic syndrome. Despite its prevalence, the pathogenesis of HSPN remains incompletely understood, and the mechanisms underlying glucocorticoid therapy are not fully elucidated. This study aimed to explore the role of p300, a key transcriptional coactivator, in the pathogenesis of HSPN and its potential as a target for glucocorticoid therapy.
Background and Rationale
HSPN is associated with aberrant immune function, including T lymphocyte dysfunction, humoral immune disorders, abnormal cytokine secretion, inflammation, coagulation, and fibrinolysis abnormalities. Renal involvement and its severity are critical indicators of long-term prognosis in HSPN. Glucocorticoids, which have both anti-inflammatory and immunosuppressive effects, are routinely used in the treatment of HSPN, particularly in the acute stage. However, the mechanisms by which glucocorticoids exert their therapeutic effects are not fully understood.
p300 is a key regulator in the transcriptional activation of glucocorticoids. It is expressed in the nuclear membrane and amplifies the effects of target genes by binding to nuclear receptors and transcription-related proteins. p300 promotes target gene transcription through histone acetylation, which alleviates promoter inhibition mediated by chromatin structure and stabilizes the transcription complex. p300 also plays a role in DNA replication, repair, cell cycle regulation, and apoptosis. Importantly, p300 enhances the transcriptional activation of glucocorticoid receptors (GRs), suggesting its potential involvement in the therapeutic effects of glucocorticoids in HSPN.
Study Design and Methods
The study utilized 48 C57BL/6N male mice, aged 3–4 weeks and weighing 18–20 grams. The mice were divided into six groups: Group I (normal control), Group II (HSPN model), Group III (HSPN model treated with dexamethasone), Group IV (p300 knockout control), Group V (p300 knockout HSPN model), and Group VI (p300 knockout HSPN model treated with dexamethasone). The HSPN model was established by administering bovine serum albumin (BSA), lipopolysaccharide (LPS), and carbon tetrachloride (CCl4) to induce renal injury. Dexamethasone was administered intraperitoneally to assess its therapeutic effects.
Renal function was assessed by measuring serum IgA, creatinine (Cr), circulating immune complex (CIC) concentrations, 24-hour urinary protein, and urinary erythrocyte counts. Renal tissue morphology was evaluated using hematoxylin-eosin (HE) staining. The expression of p300, GRα, GRβ, transforming growth factor (TGF)-β1, and activator protein (AP)-1 was determined using real-time polymerase chain reaction (PCR) and Western blotting.
Key Findings
p300 Expression in HSPN
The study found that p300 expression was significantly upregulated in the HSPN model group (Group II) compared to the normal control group (Group I). This upregulation was observed at both the mRNA and protein levels, indicating that p300 plays a crucial role in the pathogenesis of HSPN. In p300 knockout mice (Groups IV and V), p300 expression was nearly absent, confirming the accuracy of the knockout model.
Renal Injury and p300 Knockout
Renal injury was significantly alleviated in p300 knockout mice (Group V) compared to non-knockout mice (Group II). Specifically, urinary erythrocyte count, 24-hour urinary protein, serum IgA, and CIC concentrations were markedly reduced in Group V. The renal pathologic score, assessed using HE staining, also decreased significantly in p300 knockout mice. These findings suggest that p300 is involved in the pathogenesis of HSPN and that its down-regulation can mitigate renal injury.
Glucocorticoid Therapy and p300
The study further investigated the relationship between p300 and glucocorticoid therapy. In p300 knockout mice treated with dexamethasone (Group VI), the levels of urinary erythrocyte count and serum IgA were significantly higher compared to non-knockout mice treated with dexamethasone (Group III). This indicates that p300 knockdown reduces the therapeutic efficacy of dexamethasone in HSPN. Additionally, the expression of GRα was significantly increased in p300 knockout mice after dexamethasone treatment, while GRβ expression remained unchanged. This suggests that p300 interacts with GRα to mediate the therapeutic effects of glucocorticoids.
Glucocorticoid Resistance
The study also explored the role of p300 in glucocorticoid resistance. The expression of resistance genes, including TGF-β1 and AP-1, was significantly increased in p300 knockout mice. This suggests that p300 down-regulation may contribute to glucocorticoid resistance by upregulating these resistance genes. Therefore, p300 plays a crucial role in preventing glucocorticoid resistance in HSPN.
Discussion
The findings of this study highlight the critical role of p300 in the pathogenesis of HSPN and its potential as a target for glucocorticoid therapy. p300 is involved in the transcriptional activation of glucocorticoid receptors, and its down-regulation can mitigate renal injury and enhance the therapeutic effects of glucocorticoids. However, p300 knockdown also increases the expression of resistance genes, such as TGF-β1 and AP-1, which may contribute to glucocorticoid resistance.
The study provides valuable insights into the molecular mechanisms underlying HSPN and the therapeutic effects of glucocorticoids. By elucidating the role of p300 in these processes, the study opens new avenues for the development of targeted therapies for HSPN. Future research should focus on further exploring the molecular pathways involving p300 and its potential as a therapeutic target in HSPN and other renal diseases.
Conclusion
In conclusion, p300 plays a crucial role in the pathogenesis of HSPN and is a promising target for glucocorticoid therapy. p300 down-regulation can mitigate renal injury and enhance the therapeutic effects of glucocorticoids by interacting with GRα. However, p300 knockdown also increases the expression of resistance genes, which may contribute to glucocorticoid resistance. These findings provide a foundation for the development of targeted therapies for HSPN and other renal diseases.
doi.org/10.1097/CM9.0000000000000380
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