Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy

BACKGROUND AND PURPOSE: The combination of Chinese herbs, Astragali Radix and Angelicae Sinensis Radix, could alleviate renal interstitial fibrosis. Astragaloside IV (AS-IV) and ferulic acid (FA) are the two major active constituents in this combination. In this study, we employed rats with unilateral ureteral obstruction to determine whether AS-IV and FA have the same renoprotective effects and investigated the mechanisms of this action. EXPERIMENTAL APPROACH: Renal pathological changes were evaluated after treatment with AS-IV, FA or AS-IV + FA (AF) for 10 days. Meanwhile, the expression of transforming growth factor β(1) (TGF-β(1)), fibronectin, α-smooth muscle actin (α-SMA), phosphorylation of c-Jun NH(2)-terminal kinase (p-JNK) and nitric oxide (NO) production in kidney were determined. The expressions of fibronectin, α-SMA, mitogen-activated protein kinases [JNK, extracellular signal-regulated kinases (ERK), P38] in TGF-β(1)-treated NRK-49F cells or interleukin-1-treated HK-2 cells after AS-IV, FA or AF were assessed. KEY RESULTS: AF alleviated the infiltration of mononuclear cells, tubular atrophy and interstitial fibrosis; reduced the expression of fibronectin, α-SMA, TGF-β(1) and p-JNK; and dramatically increased the production of NO in obstructed kidneys. Neither AS-IV nor FA alone improved renal damage, but both increased NO production. AF inhibited α-SMA and fibronectin expression in NRK-49F or HK-2 cells. Furthermore, AF significantly inhibited IL-1β-induced JNK phosphorylation, without affecting ERK or P38 phosphorylation. Neither AS-IV nor FA alone had any effect on the cells. CONCLUSIONS AND IMPLICATIONS: AS-IV synergizes with FA to alleviate renal tubulointerstitial fibrosis; this was associated with inhibition of tubular epithelial–mesenchymal transdifferentiation (EMT) and fibroblast activation, as well as an increase in NO production in the kidney.