Dihydroartemisinin attenuates renal fibrosis through regulation of fibroblast proliferation and differentiation.
AIMS
Renal fibrosis is the most common final stage of progressive renal disease, characterized by fibroblast proliferation, fibroblast-to-myofibroblast differentiation and excessive accumulation of extracellular matrix. Dihydroartemisinin (DHA) exerts antitumor, antibacterial, and antifibrotic effects. The aim of this study was to determine whether DHA has beneficial effects on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice and to examine explore the underlying possible mechanisms.


MATERIALS AND METHODS
Eight-week-old male C57BL/6 mice were intragastrically administered DHA for 14 consecutive days after UUO operation. Afterward, interstitial collagen deposition, expression of collagen I and III, fibronectin, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and S100 calcium-binding protein A4 (S100A4) were assessed in the kidneys. Transforming growth factor beta 1 (TGF-β1)-induced primary human kidney fibroblasts were treated with DHA to further investigate the mechanism underlying its action.


KEY FINDINGS
In vivo, DHA reduced UUO-induced morphological and pathological changes and the degree of renal fibrosis. In addition, DHA mitigated fibroblast proliferation and differentiation in kidney tissue induced by UUO. In vitro, DHA significantly attenuated the TGF-β1-induced primary human kidney fibroblast proliferation and fibroblast-to-myofibroblast differentiation. Moreover, treatment with DHA attenuated the up-regulation of phosphorylation of phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) in UUO model and TGF-β1-induced primary human kidney fibroblasts.


SIGNIFICANCE
We provide in vivo and in vitro evidence that DHA may relieve renal fibrosis through regulation of fibroblast proliferation and differentiation by mitigating the PI3K/AKT pathway. DHA may potentially be used as a therapeutic antifibrotic agent for the treatment of renal fibrosis.
['Zhang|Bo|B|', 'Liu|Peihua|P|', 'Zhou|Yan|Y|', 'Chen|Zhi|Z|', 'He|Yao|Y|', 'Mo|Miao|M|', 'Dai|Guoyu|G|', 'Xia|Weiping|W|', 'Du|Yongchao|Y|', 'Liu|Yuhang|Y|', 'Chen|Xiang|X|']
D000818:Animals D037621:Artemisinins D002454:Cell Differentiation D049109:Cell Proliferation D004195:Disease Models, Animal D005347:Fibroblasts D005355:Fibrosis D007668:Kidney D008297:Male D008810:Mice, Inbred C57BL D019869:Phosphatidylinositol 3-Kinases D051057:Proto-Oncogene Proteins c-akt D014517:Ureteral Obstruction
Dihydroartemisinin Renal fibrosis Fibroblast Proliferation Differentiation Unilateral ureteral obstruction PI3K/AKT TGF-β1