IN-1130, a novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy

Abstract

The transforming growth factor-beta (TGF-beta) plays a central role in the progression of renal fibrosis. TGF-beta transduces its signal through the activin receptor-like kinase (ALK)5. IN-1130, a novel small molecule ALK5 inhibitor, inhibited the purified kinase domain of ALK5-mediated Smad3 phosphorylation with an IC(50) value of 5.3 nM. IN-1130 proved to be highly selective in a panel of 27 serine/threonine and tyrosine kinases including p38alpha mitogen-activated protein kinase. We evaluated the efficacy of IN-1130 to block renal fibrogenesis induced by unilateral ureteral obstruction (UUO) in rats. Either vehicle (saline) or IN-1130 (10 and 20 mg/kg/day) was intraperitoneally administered to UUO rats for 7 and 14 days. Phosphorylated Smad2 (pSmad2) and markers of fibrosis were analyzed in kidney tissues. In UUO control kidneys, interstitial fibrosis including tubular atrophy, loss and dilation, inflammatory cell infiltration, and fibroblast cell proliferation was prominent. These morphological changes were notably reduced by IN-1130 treatment. IN-1130 decreased levels of TGF-beta1 messenger RNA (mRNA), type I collagen mRNA, and pSmad2, compared to UUO control rats. As determined by measuring the hydroxyproline content, total kidney collagen amount was increased in UUO control kidneys, but significantly reduced by IN-1130 treatment, which was comparable to results of histochemical staining for collagen. IN-1130 also suppressed the expression of alpha-smooth muscle actin (alpha-SMA) and fibronectin in UUO kidneys. Our results show that IN-1130 suppressed the fibrogenic process of UUO, further underscoring the potential clinical benefits of IN-1130 in the treatment of renal fibrosis.

Retraction: GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β–Induced Smad3 Phosphorylation

“…25,26 Tubulointerstitial injury progressed in UUO kidneys at day 14. The morphologic changes were accompanied by increases in Smad3 phosphorylation and expression of a-SMA, collagen, and fibronectin.…”

Salt-inducible kinase 1 is involved in high glucose-induced mesangial cell proliferation mediated by the ALK5 signaling pathway

“…Additionally, TGF-β specifically induces the expression of the large modular glycoprotein, fibronectin (FN), and the antifibrinolytic agent, plasminogen activator inhibitor type 1 (PAI-1), resulting in cellular proliferation and ECM accumulation (5). A number of studies have shown that the selective inhibition of ALK5 may be a potential therapeutic strategy for the treatment of chronic renal disease secondary to diabetic nephropathy (6,7).…”

Anosmin-1 involved in neuronal cell migration is hypoxia inducible and cancer regulated

“…8 TGFβ has long been known to be associated with cell proliferation, differentiation, migration, apoptosis as well as cancer pathogenesis and progression. [9][10][11] Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the US. 12 Though TGFβ serves as a tumor suppressor in the normal intestinal epithelium by inhibiting cell proliferation and inducing apoptosis, there exists a strong correlation between the degree of differentiation of colon carcinoma cell lines and sensitivity to the antiproliferative and differentiationpromoting effects of TGFβ.…”