The feedback loop between miR-21, PDCD4 and AP-1 functions as a driving force for renal fibrogenesis

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Renal fibrosis is a common outcome of chronic kidney disease.
• Fibroblast activation is crucial in fibrosis progression, but its drivers are not fully understood.
• MicroRNA 21 (miR-21) has been implicated in kidney fibrosis progression.

Purpose of the Study:

• To investigate the precise role of miR-21 in fibroblast activation and renal fibrosis.
• To elucidate the auto-regulatory mechanisms maintaining miR-21 overexpression.
• To evaluate miR-21 as a therapeutic target for renal fibrosis.

Main Methods:

• Analysis of miR-21 levels in activated fibroblasts.
• Investigation of the auto-regulatory loop involving miR-21, PDCD4, and AP-1.
• Assessment of TGF-β1/Smad pathway activation.
• Treatment with miR-21 antagomir and AP-1 inhibitors in a unilateral ureteral obstruction (UUO) model.
• Evaluation of renal fibrosis in miR-21-knockout mice.

Main Results:

• miR-21 was significantly upregulated in activated fibroblasts and maintained by an auto-regulatory loop.
• Upregulated miR-21 suppressed Smad7, enhancing the TGF-β1/Smad pathway and promoting fibroblast activation.
• miR-21 sequestration or AP-1 inhibition attenuated UUO-induced renal fibrosis.
• miR-21-knockout mice exhibited reduced interstitial fibrosis after kidney injury.

Conclusions:

• miR-21 is a key driver of fibroblast activation and renal fibrosis.
• A double negative autoregulatory loop maintains high miR-21 expression.
• Targeting the miR-21 feedback loop offers a potential therapeutic strategy for fibrotic kidney disease.