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JMJD3 ablation in myeloid cells confers renoprotection in mice with DOCA/salt-induced hypertension
Ying Gao1, Wenqiang Yu2, Jinfang Song3
1Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China.
Insights
Targeting Jumonji domain containing-3 (JMJD3) in myeloid cells can reduce kidney inflammation and fibrosis associated with deoxycorticosterone acetate (DOCA)/salt-induced hypertension, offering a potential therapeutic strategy.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Hypertension causes kidney injury through inflammation and fibrosis.
- Jumonji domain containing-3 (JMJD3) is implicated in inflammatory responses and fibrogenesis.
Purpose of the Study:
- To investigate the role of myeloid JMJD3 in kidney inflammation and fibrosis during deoxycorticosterone acetate (DOCA)/salt-induced hypertension.
- To evaluate the therapeutic potential of myeloid JMJD3 inhibition.
Main Methods:
- Utilized myeloid-specific JMJD3-deficient mice and wild-type controls.
- Induced hypertension using deoxycorticosterone acetate (DOCA)/salt regimen.
- Assessed kidney function, injury markers, inflammation, fibrosis, and cell activation.
Main Results:
- JMJD3 expression increased in kidneys with hypertensive injury.
- Myeloid JMJD3 deficiency ameliorated kidney function and injury.
- Reduced collagen deposition, extracellular matrix expression, and fibroblast activation in deficient mice.
- Blunted inflammatory response and myeloid myofibroblast activation, including macrophage-to-myofibroblast transition.
- Decreased interferon regulator factor 4 expression.
Conclusions:
- Myeloid JMJD3 deficiency protects against kidney inflammation and fibrosis in DOCA/salt-induced hypertension.
- Inhibiting myeloid JMJD3 is a potential therapeutic target for hypertensive nephropathy.
Abstract:
Hypertension-induced renal injury is characterized by robust inflammation and tubulointerstitial fibrosis. Jumonji domain containing-3 (JMJD3) is closely linked with inflammatory response and fibrogenesis. Here we examined the effect of myeloid JMJD3 ablation on kidney inflammation and fibrosis in deoxycorticosterone acetate (DOCA)/salt hypertension. Our results showed that JMJD3 is notably induced in the kidneys with hypertensive injury. DOCA/salt stress causes an elevation in blood pressure that was no difference between myeloid specific JMJD3-deficient mice and wild-type control mice. Compared with wild-type control mice, myeloid JMJD3 ablation ameliorated kidney function and injury of mice in response to DOCA/salt challenge. Myeloid JMJD3 ablation attenuated collagen deposition, extracellular matrix proteins expression, and fibroblasts activation in injured kidneys following DOCA/salt treatment. Furthermore, myeloid JMJD3 ablation blunts inflammatory response in injured kidneys after DOCA/salt stress. Finally, myeloid JMJD3 ablation precluded myeloid myofibroblasts activation and protected against macrophages to myofibroblasts transition in injured kidneys. These beneficial effects were accompanied by reduced expression of interferon regulator factor 4. In summary, JMJD3 ablation in myeloid cells reduces kidney inflammation and fibrosis in DOCA salt-induced hypertension. Inhibition of myeloid JMJD3 may be a novel potential therapeutic target for hypertensive nephropathy. Myeloid JMJD3 deficiency reduces inflammatory response, myeloid fibroblasts activation, macrophages to myofibroblasts transition, and delays kidney fibrosis progression.
