Triptolide Attenuates Renal Tubular Epithelial-mesenchymal Transition Via the MiR-188-5p-mediated PI3K/AKT Pathway in Diabetic Kidney Disease

Abstract

Triptolide possesses the trait of renal protection. Epithelial-mesenchymal transition (EMT) is closely linked to the pathogenesis of diabetic kidney disease (DKD). MicroRNAs have recently emerged as critical regulators of DKD. However, it is poorly understood whether triptolide alleviates renal EMT by regulating microRNAs in DKD. In this study, we found that triptolide decreased albuminuria, improved the renal structure and reduced renal EMT in rats with DKD. Furthermore, activation of the PI3K/AKT signaling pathway was increased in diabetic rats, which was partly reversed by triptolide. Triptolide also alleviated glucose-induced EMT in HK-2 cells in vitro. PI3K/AKT signaling pathway activation was reduced after triptolide treatment. Moreover, triptolide decreased the increase in miR-188-5p expression stimulated by high glucose levels in HK-2 cells. miR-188-5p inhibited PTEN expression by directly interacting with the PTEN 3'-untranslated region. Additionally, downregulation of miR-188-5p, which imitates the effects of triptolide, attenuated the activation of the PI3K/AKT pathway and HG-induced EMT, whereas miR-188-5p overexpression reversed the effects of triptolide on the PI3K/AKT pathway and EMT. In conclusion, we demonstrated that triptolide ameliorates renal EMT via the PI3K/AKT signaling pathway through the interaction between miR-188-5p and PTEN, indicating that miR-188-5p may be a therapeutic target of triptolide in DKD.

miR‐188‐5p emerges as an oncomiRNA to promote gastric cancer cell proliferation and migration via upregulation of SALL4

“…A study has shown that miR-188-5p binded to the 3′UTR of PTEN to activate the PI3K/AKT signaling pathway and promote EMT in diabetic Kidney disease. 19 Therefore, we chose PTEN as a candidate target for further validation. Surprisingly, luciferase reporter detection failed to validate that PTEN was the target gene of miR-188-5p.…”

Anti-apoptosis mechanism of triptolide based on network pharmacology in focal segmental glomerulosclerosis rats

“…TPL has anti-inflammatory, anti-tumor, and immunologic effects on many diseases [4]. TPL inhibits the secretion of many cytokines, adhesion molecules, and chemokines and affects the functions of various cells, including dendritic cells and renal tubular epithelial cells [5,6]. TPL has been reported to alleviate the progression of glomerulosclerosis and the excretion rate of urinary albumin to inhibit the progression…”

Urinary Exosomal MicroRNA Signatures in Nephrotic, Biopsy-Proven Diabetic Nephropathy

“…In a cell culture model, miR-188-5p is shown to regulate high glucose-induced epithelial-mesenchymal transition (EMT) in human proximal tubular cell lines through the PTEN/PI3K/Akt pathway [21]. By analyzing miRs from the patients' urine exosomes, we demonstrated the pathologic role of miR-188-5p in nephrotic and biopsy-proven isolated DN.…”

“…The strongest up-regulation that we identified in the urine exosomes of the nephrotic, isolated DN patients was with miR-188-5p. This miR has been reported to regulate the high glucose-induced epithelial-mesenchymal transition of HK-2 cells through the PTEN/PI3K/Akt pathway [21]. The second most strongly up-regulated miR was miR-150-3p.…”