Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

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.

Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments

“…No differences in body weight are generally observed from UUO [20]. In the UUO-OKs, by compiling this review article we have noted an interesting phenomenon regarding kidney weight: in mice, UUO-OKs end up weighing less than Sham kidneys [1,30,31]; but in rats, UUO-OKs weigh more than Sham kidneys [9,10,16]. (Kidney weight is expressed as the kidney weight-to-body weight ratio).…”

“…Klotho is a protein bound to the membrane of kidney distal tubules that has anti-fibrotic effects in the kidney [20]. During UUO, Klotho protein levels are reduced [31]. Acetylated-α-tubulin, α-tubulin and vimentin protein levels have been determined to evaluate altered microtubules [53].…”

“…Acetyl-11-keto-β-boswellic acid or “AKBA” (PubChem CID 11168203) is a pentacyclic triterpenoid compound that can be extracted from the plant Boswellia serrata (Burseraceae). Liu et al [31] found that, compared to untreated UUO-OKs, AKBA-treated UUO-OKs showed decreased SCr and BUN levels; reduced protein levels of α-SMA, TGF-β 1 , collagen I, collagen IV, Smad 2/3, TGF-β type I and II receptors (TGF-βRI and TGF-βRII), p-Smad2/3 and Smad4; while increasing protein levels of Klotho and Smad7. AKBA has an effect over the Klotho/TGF-β 1 /Smad pathway [31].…”

Protective effect of miRNA-containing extracellular vesicles derived from mesenchymal stromal cells of old rats on renal function in chronic kidney disease

“…The main pathological change in CKD is renal fibrosis, and TGF-β1 is widely regarded as the key cytokine that promotes fibrosis [39]. HK2 is an established human kidney epithelial cell line, and TGF-β1-induced HK2 cells were used to imitate the pathological process of renal fibrosis in vitro in several studies [40,41]. TGF-β1 induces the transformation of tubular epithelial cells to fibroblast cells, downregulates E-cadherin expression and upregulates SMA expression [42].…”

Identifying the Growth Factors for Improving Neointestinal Regeneration in Rats through Transcriptome Analysis Using RNA-Seq Data

“…Previous studies have identified several new SMAD gene targets among which are COL1A1, COL3A1, COL5A2, COL6A1, COL6A3, and TIMP-1 [69]. Most notably, the SMAD signaling pathway is crucial for simultaneous activation of several fibrillar collagen genes by TGF- β [70]. Besides playing a part in the regulation of the expression of ECM components, SMAD has recently been identified as capable of mediating the inhibitory activity of TGF- β on interstitial collagenase (matrix metalloproteinase-1) gene activation by proinflammatory cytokine [71, 72].…”