Role of p300 in the pathogenesis of Henoch-Schonlein purpura nephritis and as a new target of glucocorticoid therapy in mice
Ming-Yu Jiang¹,², Wei Li¹, Xiang-Ping Xu², Jie-Qing Zhou¹, Hong Jiang¹
¹Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China; ²Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
Henoch-Schonlein purpura nephritis (HSPN) is one of the most common secondary kidney diseases in children, affecting up to 100% of kids with Henoch-Schonlein purpura (HSP)—a chronic vasculitis that causes skin purpura, joint pain, and gastrointestinal issues. While glucocorticoids like dexamethasone are standard treatments for HSPN, exactly how they work—and why some children develop resistance—isn’t fully understood. A 2019 study by researchers from China Medical University and Harbin Medical University set out to solve part of this puzzle by exploring the role of a protein called p300 in HSPN’s development and glucocorticoid therapy.
What is p300?
p300 is a key regulator of gene activity. It acts as a “bridge” between transcription factors (proteins that control when genes turn on or off) and the cell’s DNA-reading machinery. It also modifies histones—proteins that package DNA—to make genes more accessible for transcription. For glucocorticoids, p300 amplifies their effects by interacting with glucocorticoid receptors (GRs), which are proteins that bind to these hormones and trigger anti-inflammatory and immunosuppressive responses.
How the Study Was Done
The team used 48 male C57BL/6N mice (3–4 weeks old) split into six groups to test p300’s role:
- Normal control: Given plain solvents (no HSPN induction).
- HSPN model: Induced with sensitizing drugs (bovine serum albumin, lipopolysaccharide, carbon tetrachloride) to mimic HSPN.
- HSPN + dexamethasone: HSPN model mice treated with 1 mg/kg dexamethasone (a glucocorticoid) daily for 4 weeks.
- p300 knockout control: Mice with kidney-specific p300 deletion, given plain solvents.
- p300 knockout HSPN: p300 knockout mice induced with HSPN.
- p300 knockout + dexamethasone: p300 knockout HSPN mice treated with dexamethasone.
All animal procedures followed ethical guidelines and were approved by China Medical University’s Institutional Animal Care and Use Committee.
To measure kidney health, the team checked:
- Biochemical markers: Urinary erythrocytes (blood in urine), 24-hour protein (proteinuria), serum IgA (a key immune protein in HSPN), creatinine (kidney function), and circulating immune complexes (CICs—immune proteins that damage kidneys).
- Gene and protein activity: Real-time PCR (to measure p300, GRs, and resistance genes) and Western blotting (to measure protein levels).
- Kidney damage: Hematoxylin-eosin (HE) staining of kidney tissue, scored using a semi-quantitative system for inflammation, fibrosis, and scarring.
Key Results
The study uncovered three critical findings about p300’s role in HSPN:
1. p300 is overactive in HSPN
HSPN model mice (Group 2) had 2–3 times more p300 mRNA and protein than normal controls (Group 1). This confirms p300 is a driver of HSPN’s development.
2. Knocking out p300 reduces kidney injury
When p300 was deleted in HSPN mice (Group 5), kidney damage dropped dramatically compared to non-knockout HSPN mice (Group 2):
- Urinary erythrocytes: 9.7 vs. 18.7 per high-power field (less blood in urine).
- 24-hour protein: 0.18 vs. 0.36 g (less protein leakage).
- Serum IgA: 18.8 vs. 38.5 mg/mL (lower immune activity).
- CICs: 0.8 vs. 1.64 mg/mL (fewer harmful immune complexes).
- Kidney damage score: 7 vs. 18 (less inflammation, fibrosis, and scarring).
These results prove p300 is essential for HSPN-related kidney injury—without it, the disease is less severe.
3. Dexamethasone works worse without p300
Glucocorticoids rely on p300 to function. When p300 was knocked out, dexamethasone’s benefits faded:
- Urinary erythrocytes: 9.2 vs. 3.7 per high-power field (more blood in urine in knockout mice).
- Serum IgA: 27.9 vs. 12.4 mg/mL (higher immune activity in knockout mice).
Knocking out p300 also increased two genes linked to glucocorticoid resistance:
- TGF-b1: A protein that drives kidney fibrosis (scarring).
- AP-1: A transcription factor that promotes inflammation.
This suggests p300 normally keeps these resistance genes in check by binding to GRα—the active form of the glucocorticoid receptor. Without p300, GRα can’t block these harmful pathways, making glucocorticoids less effective.
Why This Matters
The study ties p300 directly to HSPN’s root causes. p300’s overactivity in HSPN likely drives the immune and inflammatory processes that damage kidneys. Knocking it out reduces that damage, proving it’s a key player.
For treatment, p300 is a linchpin. Glucocorticoids work by binding to GRα, but GRα needs p300 to activate anti-inflammatory genes and block resistance genes like TGF-b1 and AP-1. Without p300, glucocorticoids can’t protect kidneys as well—and resistance becomes more likely.
This is a big step forward for kids with HSPN, especially those who don’t respond to standard glucocorticoids. Targeting p300 could make existing therapies more effective or even lead to new treatments that tackle HSPN at its genetic core.
Conclusion
p300 is critical to both the development of HSPN and the effectiveness of glucocorticoid therapy. By binding to GRα and suppressing resistance genes, p300 helps glucocorticoids protect kidneys. The study suggests p300 could be a new target to improve HSPN treatment—offering hope for better outcomes in children with this common kidney disease.
Ming-Yu Jiang, Wei Li, Xiang-Ping Xu, Jie-Qing Zhou, Hong Jiang. Role of p300 in the pathogenesis of Henoch-Schonlein purpura nephritis and as a new target of glucocorticoid therapy in mice. Chinese Medical Journal 2019;132(16):1942–1950. doi:doi.org/10.1097/CM9.0000000000000380
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