Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• Chronic kidney disease (CKD) is characterized by fibrosis, a process lacking effective treatments.
• Relaxin shows promise as an antifibrotic therapy, but its mechanism remains unclear.
• Transforming growth factor-β1 (TGF-β1) is a key profibrotic mediator.

Purpose of the Study:

• To investigate the interaction between relaxin and the angiotensin II type 2 receptor (AT2R).
• To elucidate the signaling pathway through which relaxin exerts its antifibrotic effects in the context of kidney fibrosis.

Main Methods:

• Primary rat kidney myofibroblasts were used for in vitro studies.
• In vivo experiments involved relaxin treatment in wild-type and AT2R-knockout mice subjected to unilateral ureteric obstruction.
• The AT2R antagonist PD123319 was employed to assess relaxin's activity.

Main Results:

• Relaxin's antifibrotic effects were significantly inhibited by the AT2R antagonist PD123319, both in vitro and in vivo.
• Administration of relaxin to AT2R-knockout mice abolished its antifibrotic actions.
• Relaxin signals through RXFP1-AT2R heterodimers, not direct binding to AT2R, to mediate antifibrotic effects.

Conclusions:

• Relaxin's antifibrotic actions in kidney fibrosis are dependent on its interaction with the AT2R.
• RXFP1 and AT2R form functional heterodimers that mediate relaxin's antifibrotic signaling.
• This novel RXFP1-AT2R interaction represents a potential therapeutic target for managing kidney fibrosis.