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mPGES-1-derived PGE2 contributes to adriamycin-induced podocyte injury
Jing Yu1, Wei Gong1, Yimei Wu1
1Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and Nanjing Key Laboratory of Pediatrics, Nanjing, China.
Abstract:
Podocyte damage is a common pathological feature in many types of glomerular diseases and is involved in the occurrence and progression of kidney disease. However, the pathogenic mechanisms leading to podocyte injury are still uncertain. The present study was undertaken to investigate the role of microsomal PGE synthase (mPGES)-1 in adriamycin (ADR)-induced podocyte injury as well as the underlying mechanism. In both mouse kidneys and in vitro podocytes, application of ADR remarkably enhanced mPGES-1 expression in line with a stimulation of cyclooxygenase-2. Interestingly, inhibition of mPGES-1 with a small interfering RNA approach significantly attenuated ADR-induced downregualtion of podocin and nephrin. Moreover, ADR-induced podocyte apoptosis was also markedly blocked in parallel with blunted caspase-3 induction. In agreement with the improvement of cell phenotypic alteration and apoptosis, the enhanced inflammatory markers of IL-1β and TNF-α were also significantly suppressed by mPGES-1 silencing. More importantly, in mPGES-1-deficient mice, albuminuria induced by ADR showed a remarkable attenuation in line with decreased urinary output of PGE2 and TNF-α, highly suggesting an in vivo role of mPGES-1 in mediating podocyte injury. In summary, findings from the present study offered the first evidence demonstrating a pathogenic role of mPGES-1 in mediating ADR-induced podocyte injury possibly via triggering an inflammatory response.
Insights
Microsomal prostaglandin E synthase-1 (mPGES-1) plays a key role in adriamycin-induced kidney injury by promoting podocyte damage and inflammation. Inhibiting mPGES-1 protects against this injury.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- Podocyte damage is central to glomerular diseases and kidney disease progression.
- The precise mechanisms driving podocyte injury remain unclear.
- Microsomal prostaglandin E synthase-1 (mPGES-1) is implicated in inflammatory processes.
Purpose of the Study:
- To investigate the role of mPGES-1 in adriamycin (ADR)-induced podocyte injury.
- To elucidate the underlying pathogenic mechanisms involving mPGES-1.
Main Methods:
- Studied mPGES-1 and cyclooxygenase-2 expression in ADR-treated mouse kidneys and cultured podocytes.
- Utilized small interfering RNA (siRNA) to inhibit mPGES-1.
- Assessed podocyte markers (podocin, nephrin), apoptosis (caspase-3), and inflammatory cytokines (IL-1β, TNF-α).
- Evaluated ADR-induced albuminuria and urinary PGE2/TNF-α in mPGES-1-deficient mice.
Main Results:
- ADR increased mPGES-1 and cyclooxygenase-2 expression in podocytes and kidneys.
- mPGES-1 inhibition via siRNA attenuated ADR-induced podocin/nephrin downregulation and podocyte apoptosis.
- Silencing mPGES-1 reduced ADR-induced IL-1β and TNF-α levels.
- mPGES-1-deficient mice exhibited reduced ADR-induced albuminuria, PGE2, and TNF-α excretion.
Conclusions:
- mPGES-1 is a significant mediator of adriamycin-induced podocyte injury.
- mPGES-1 appears to exert its pathogenic effects by triggering inflammatory responses.
- These findings highlight mPGES-1 as a potential therapeutic target in kidney disease.
