Intermedin is upregulated and attenuates renal fibrosis by inhibition of oxidative stress in rats with unilateral ureteral obstruction

Abstract Aim Transforming growth factor‐β1 ( TGF ‐β1) plays a pivotal role in the progression of renal fibrosis. Reactive oxygen species mediate profibrotic action of TGF ‐β1. Intermedin ( IMD ) has been shown to inhibit oxidative stress, but its role in renal fibrosis remains unclear. Here, we investigated the effects of IMD on renal fibrosis in a rat model of unilateral ureteral obstruction ( UUO ). Methods The expression of IMD and its receptors, calcitonin receptor‐like receptor ( CRLR ) and receptor activity‐modifying proteins ( RAMP 1/2/3), in the obstructed kidney was detected by real‐time polymerase chain reaction (PCR) , western blotting and immunohistochemistry. To evaluate the effects of IMD on renal fibrosis, we locally overexpressed exogenous IMD in the obstructed kidney using an ultrasound‐microbubble‐mediated delivery system. Renal fibrosis was determined by Masson trichrome staining. The expression of TGF ‐β1, connective tissue growth factor ( CTGF) , α‐smooth muscle actin (α‐ SMA) and fibronectin was measured. Smad2/3 activation and macrophage infiltration were evaluated. We also studied oxidative stress by measuring superoxide dismutase ( SOD) activity and malondialdehyde ( MDA) content. Results mRNA and protein expression of IMD increased after UUO . CRLR , RAMP1 , RAMP2 and RAMP3 were also induced by ureteral obstruction. IMD overexpression remarkably attenuated UUO ‐induced tubular injury and blunted fibrotic response as shown by decreased interstitial collagen deposition and downregulation of fibronectin. Macrophage infiltration, α‐ SMA and CTGF upregulation caused by UUO were all relieved by IMD , whereas TGF ‐β1 upregulation and S mad2/3 activation were not affected. Meanwhile, we noted increased oxidative stress in obstruction, which was also attenuated by IMD gene delivery. Conclusions Our results indicate that IMD is upregulated after UUO . IMD plays a protective role in renal fibrosis via its antioxidant effects.