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Protective effects of FR167653 on chronic allograft nephropathy by inhibiting p38 MAPK in rats
1Second Hospital of Hebei Medical University, Department of Nephrology, Shijiazhuang, Hebei Province, PR China. huibintan@163.com
Background:
Chronic allograft nephropathy (CAN) remains a challenge for transplant clinicians. Some novel intervention strategies may shed new light on its treatment.
Methods:
An orthotopic kidney transplant model in Fisher-to-Lewis rats was used with administration of cyclosporine alone or in combination with FR167653 (30 mg/kg/d subcuntaneously) to recipients. We analyzed renal function and urinary protein excretion. Animals were sacrificed at 30 weeks posttransplantation for histological and immunohistochemical studies.
Results:
Renal function among vehicle-treated rats deteriorated progressively with substantial proteinuria compared with FR167653-treated rats. FR167653 administration significantly prevented the morphlogical features of CAN and prolonged rat survivals. p38 mitogen-activated protein kinase (MAPK) expression was markedly reduced by FR167653 treatment. Meanwhile, transforming growth factor-beta1 and monocyte chemotactic protein-1 expression were significantly down-regulated among FR167653-treated hosts.
Conclusion:
p38 MAPK phosphorylation correlated with CAN progression and inhibition of p38 MAPK by FR167653 may provide a potent novel therapeutic target for its prevention.
Insights
FR167653 effectively prevents chronic allograft nephropathy (CAN) in kidney transplants by inhibiting p38 mitogen-activated protein kinase (MAPK). This novel therapeutic strategy shows promise for improving transplant outcomes.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Chronic allograft nephropathy (CAN) poses a significant clinical challenge in organ transplantation.
- Novel therapeutic interventions are needed to combat CAN progression.
Purpose of the Study:
- To investigate the efficacy of FR167653 in preventing CAN.
- To explore the role of p38 MAPK in CAN development and the effect of FR167653 on its expression.
Main Methods:
- An orthotopic kidney transplant rat model was utilized.
- Cyclosporine with or without FR167653 was administered.
- Renal function, proteinuria, and histological changes were assessed at 30 weeks.
- Immunohistochemistry was performed to evaluate protein expression.
Main Results:
- FR167653 treatment significantly improved renal function and reduced proteinuria compared to controls.
- Histological analysis showed FR167653 prevented CAN morphology and prolonged survival.
- FR167653 markedly reduced p38 MAPK phosphorylation, TGF-β1, and MCP-1 expression.
Conclusions:
- p38 MAPK phosphorylation is closely linked to CAN progression.
- Inhibiting p38 MAPK with FR167653 represents a potential therapeutic target for CAN prevention.
