Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 162, Issue 8, Pages 1805-1818Publisher
WILEY
DOI: 10.1111/j.1476-5381.2011.01206.x
Keywords
astragaloside IV; ferulic acid; renal tubulointerstitial fibrosis; mitogen-activated protein kinase; unilateral ureteral obstruction; rat; Astragali Radix; Angelicae Sinensis Radix
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Funding
- National Natural Science Foundation of China [30330710]
- Specialized Research Fund for the Doctoral Program of Higher Education [20070001761]
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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 beta(1) (TGF-beta(1)), fibronectin, alpha-smooth muscle actin (alpha-SMA), phosphorylation of c-Jun NH2-terminal kinase (p-JNK) and nitric oxide (NO) production in kidney were determined. The expressions of fibronectin, a-SMA, mitogen-activated protein kinases [JNK, extracellular signal-regulated kinases (ERK), P38] in TGF-beta 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, alpha-SMA, TGF-beta(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 a-SMA and fibronectin expression in NRK-49F or HK-2 cells. Furthermore, AF significantly inhibited IL-1 beta-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.
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