當藥黃素改善慢性腎臟病纖維化之體內外研究

高尿酸血症(hyperuricemia)已被證實是導致慢性腎臟病(chronic kidney disease, CKD)發生重要危險因子，並進一步引發腎纖維化(renal fibrosis)。在此高尿酸(uric acid, UA)環境下，氧化壓力(oxidative stress)及促發炎因子顯著增加，可能伴隨腎小球系膜細胞(glomerular mesangial cells)纖維化反應，加速CKD病理進程。當藥黃素(swertisin)為一種廣泛存在於多種藥用植物中之黃酮類化合物。根據文獻報導Swertisin具備抗氧化、抗發炎、抗糖尿病及促進認知功能等多元生物活性；然而，至今尚無針對Swertisin與CKD相關之研究發表。因此，本研究旨在探討Swertisin是否能抑制高尿酸誘導之腎纖維化，並進一步改善CKD進展。本研究首先於體內建立0.15%腺嘌呤(adenine)誘導C57BL/6小鼠腎損傷模式，並分別給予Swertisin治療與臨床用藥別嘌醇(allopurinol)作為對照。研究結果顯示，Swertisin可顯著改善小鼠腎功能，並在腎組織病理染色中觀察到腎絲球萎縮及纖維化之改善效果。進一步分析亦發現Swertisin能有效降低促發炎因子表現，並調控轉化生長因子β1 (transforming growth factor beta 1, TGF-β1)，抑制上皮間質轉化(epithelial-mesenchymal transition, EMT)及細胞外基質(extracellular matrix, ECM)過度沉積。上述結果顯示，Swertisin可藉由抑制TGF-β/Sma-and-mad關聯蛋(sma and mad related protein, Smad)訊息傳遞途徑，緩解Adenine誘發腎損傷與纖維化。此外，於體外實驗中，UA成功誘導小鼠腎絲球系膜細胞(SV40 MES 13)產生氧化壓力、發炎反應與纖維化表徵；而Swertisin之處理有效抑制上述細胞損傷反應與TGF-β/Smad訊號活化，與體內結果一致。實驗證明Swertisin能顯著抑制細胞核內Smad複合體形成與DNA結合表現。綜合以上結果，Swertisin可透過調控TGF-β/Smad訊號傳遞途徑，抑制UA誘發之腎纖維化，進而保護腎間質細胞免於損傷，最終達到延緩CKD進展之效果。

Hyperuricemia has been recognized as a critical risk factor for the onset and progression of chronic kidney disease (CKD), and it may further lead to renal fibrosis. Under the elevated uric acid (UA) conditions, oxidative stress and pro-inflammatory cytokines are significantly increased, which may directly trigger fibrosis in glomerular mesangial cells and accelerate CKD progression. Swertisin, a flavonoid compound widely found in various medicinal plants has been reported to exhibit antioxidant, anti-inflammatory, anti-diabetic, and cognitive-enhancing properties. However, to date, no studies have explored the potential role of swertisin in CKD prevention or treatment. This study investigated whether swertisin can inhibit UA-induced renal fibrosis and further evaluate its therapeutic potential in mitigating CKD progression. In the in vivo study, a renal injury model was established by administering 0.15% adenine to C57BL/6 mice. Mice were treated with swertisin, while allopurinol, a clinically used medication, served as a control of clinical drug. The results demonstrated that swertisin significantly improved renal function, and histopathological analysis revealed the reduced glomerular atrophy and fibrosis in the swertisin-treated group. Further analysis showed that swertisin effectively suppressed pro-inflammatory cytokine level and regulated transforming growth factor beta 1 (TGF-β1), thereby inhibiting epithelial-mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition. These findings suggest that swertisin alleviates UA-induced renal injury and fibrosis by suppressing the TGF-β/Smad signaling pathway. In the in vitro study, UA stimulation successfully induced oxidative stress, inflammation, and fibrosis in mouse glomerular mesangial cells (SV40 MES 13). Swertisin treatment effectively reduced the UA-induced cellular responses and suppressed TGF-β/Smad pathway activation, consistent with the in vivo findings. Furthermore, swertisin significantly inhibited nuclear Smad complex formation and DNA-binding activity. In conclusion, swertisin exerts renoprotective effects by regulating the TGF-β/Smad signaling pathway, and attenuating the UA-induced renal fibrosis, contributing to and protecting mesangial cells from injury, and ultimately delay CKD progression.