Abstract
Acetyl‐11‐keto‐β‐boswellic acid (AKBA), an active triterpenoid compound from the extract of Boswellia serrate, has been reported previously in our group to alleviate fibrosis in vascular remodelling. This study aimed to elucidate the in vivo and in vitro efficacy and mechanism of AKBA in renal interstitial fibrosis. The experimental renal fibrosis was produced in C57BL/6 mice via unilateral ureteral obstruction (UUO). Hypoxia‐induced HK‐2 cells were used to imitate the pathological process of renal fibrosis in vitro. Results showed that the treatment of AKBA significantly alleviated UUO‐induced impairment of renal function and improved the renal fibrosis by decreasing the expression of TGF‐β1, α‐SMA, collagen I and collagen IV in UUO kidneys. In hypoxia‐induced HK‐2 cells, AKBA displayed remarkable cell protective effects and anti‐fibrotic properties by increasing the cell viability, decreasing the lactate dehydrogenase (LDH) release and inhibiting fibrotic factor expression. Moreover, in obstructed kidneys and HK‐2 cells, AKBA markedly down‐regulated the expression of TGFβ‐RI, TGFβ‐RII, phosphorylated‐Smad2/3 (p‐Smad2/3) and Smad4 in a dose‐dependent fashion while up‐regulated the expression of Klotho and Smad7 in the same manner. In addition, the effects of AKBA on the Klotho/TGF‐β/Smad signalling were reversed by transfecting with siRNA‐Klotho in HK‐2 cells. In conclusion, our findings provide evidence that AKBA can effectively protect kidney against interstitial fibrosis, and this renoprotective effect involves the Klotho/TGF‐β/Smad signalling pathway. Therefore, AKBA could be considered as a promising candidate drug for renal interstitial fibrosis.
Highlights
We investigated the effect of Acetyl‐11‐keto‐β‐boswellic acid (AKBA) on ureteral obstruction (UUO)‐ induced renal interstitial fibrosis for the first time
The result showed that AKBA plays a markedly protective role against renal injury via anti‐fibrosis effects mediated by the Klotho/TGF‐β/Smad pathway
The renal protective effect and the potential mechanism of AKBA were further confirmed in hypoxia‐induced HK‐2 cells
Summary
Betulinic acid ameliorates experimental diabetic renal fibrosis by inhibiting the activation of NF‐kB signalling pathway.[12] Oleanolic acid, the similar pentacyclic triterpene compound, exerts its therapeutic effect on tubulointerstitial fibrosis in chronic cyclosporine nephropathy.[13] Another study revealed that Asiatic acid attenuates renal fibrosis by rebalancing TGF‐β/Smad signalling pathway.[14] More encouragingly, previous studies of our group have found that AKBA is beneficial for vascular remodelling and fibrosis by blocking TGF‐β/Smad pathway. This prompted us to address in greater detail the role and mechanism of AKBA in renal fibrosis. We hypothesized that AKBA would provide reno‐protection against fibrosis in UUO‐induced mice and in hypoxia‐induced HK‐2 cells, and that the protective effects were exerted through inhibiting the Klotho/TGF‐β/Smad pathway
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