SJB-003-085, a newly-synthesized Src kinase inhibitor, attenuates the progression of renal interstitial fibrosis

抄録

Background

Src family kinases (SFKs), a group of non-receptor and intracellular tyrosine kinases, are classically known as proto-oncogenes. Recent studies have suggested that SFKs are excessively activated and play an important role in the fibrosis development of various tissues, i.e. idiopathic pulmonary fibrosis, systemic sclerosis, liver fibrosis, as well as kidney fibrosis. The present study was directed to investigate the effect of SJB 003-085, a newly synthesized Src kinase inhibitor (SKI) with proposed low toxicity, in preventing the progression of renal interstitial fibrosis.

Methods

Unilateral ureteral obstruction (UUO) surgery was performed in 6-week-old male C57BL/6 mice to induce renal interstitial fibrosis. Either SJB-003-085 (30 mg/kg, oral) or PP2 (2 mg/kg, intraperitoneal injection), a common experimental SKI, was administered to the mice for 7 days, started one day prior to surgery.

Results

UUO induced SFKs expression, including Src, Fyn, Lyn, and Yes. Inhibition of SFKs by SJB significantly improved renal function and prevented the progression of tubular injury indicated by decreases in albuminuria, urinary KIM-1, and NGAL protein expression in the kidney. The development of renal interstitial fibrosis was halted in response to SJB, as shown by decreases in α-SMA, collagen I and IV protein levels along with reduced Masson's trichrome-positive tubulointerstitial area. SJB also inhibited inflammation in the UUO kidney, exhibited by reductions in F4/80 positive-stained area and p-NFκB protein level. Importantly, prevention of tubular injury, anti-fibrotic, and anti-inflammatory effect of SJB were similar to PP2, a standard experimental SKI. Unlike PP2, SJB lowered lipid peroxides, a marker of oxidative stress in the kidney.

Conclusion

SJB-003-085 is a promising agent to attenuate the progression of renal interstitial fibrosis.

Keywords:

Src Family Kinases, Src Kinase Inhibitor, UUO, renal interstitial fibrosis, kidney fibrosis