RESUMO
Background: QiHuangYiShen granules (QHYS), a traditional Chinese herbal medicine formula, have been used in clinical practice for treating diabetic kidney disease for several years by our team. The efficacy of reducing proteinuria and delaying the decline of renal function of QHYS has been proved by our previous studies. However, the exact mechanism by which QHYS exerts its renoprotection remains largely unknown. Emerging evidence suggests that lncRNA MALAT1 is abnormally expressed in diabetic nephropathy (DN) and can attenuate renal fibrosis by modulating podocyte epithelial-mesenchymal transition (EMT). Objective: In the present study, we aimed to explore whether QHYS could modulate lncRNA MALAT1 expression and attenuate the podocyte EMT as well as the potential mechanism related to the Wnt/ß-catenin signal pathway. Methods: SD rats were fed with the high-fat-high-sucrose diet for 8 weeks and thereafter administered with 30 mg/kg streptozotocin intraperitoneally to replicate the DN model. Quality control of QHYS was performed using high-performance liquid chromatography. QHYS were orally administered at 1.25, 2.5, and 5 g/kg doses, respectively, to the DN model rats for 12 weeks. Body weight, glycated haemoglobin, blood urea nitrogen, serum creatinine, 24-h proteinuria, and kidney index were measured. The morphologic pathology of the kidney was evaluated by Hematoxylin-eosin and Masson's trichrome staining. The expression level of lncRNA MALAT1 was determined by quantitative real-time polymerase chain reaction. In addition, the expression levels of podocyte EMT protein markers and Wnt/ß-catenin pathway proteins in renal tissues were evaluated by Western blotting and immunohistochemistry. Results: The results showed that QHYS significantly reduced 24-h proteinuria, blood urea nitrogen, kidney index, and ameliorated glomerular hypertrophy and collagen fiber deposition in the kidney of DN rats. Importantly, QHYS significantly downregulated the expression level of lncRNA MALAT1, upregulated the expression of nephrin, the podocyte marker protein, downregulated the expression of desmin and FSP-1, and mesenchymal cell markers. Furthermore, QHYS significantly downregulated the expression levels of Wnt1, ß-catenin, and active ß-catenin. Conclusion: Conclusively, our study revealed that QHYS significantly reduced proteinuria, alleviated renal fibrosis, and attenuated the podocyte EMT in DN rats, which may be associated with the downregulation of lncRNA MALAT1 expression and inhibition of the Wnt/ß-catenin pathway.
RESUMO
Macroangiopathy is a complication of Type II Diabetes Mellitus (T2DM), which is mainly caused by fibrosis of blood vessels. Using T2DM rat models, we investigated whether the traditional Chinese medicine, Di-Dang Decoction (DDD), exhibited anti-fibrotic actions on great vessels. T2DM rats were randomly divided into non-intervention group, early-, middle-, late-stage DDD intervention groups and control groups, including pioglitazone group and aminoguanidine group. After administration of DDD to T2DM rats at different times, we detected the amount of extracellular matrix (ECM) deposition in the thoracic aorta. The results showed that early-stage intervention with DDD could effectively protect great vessels from ECM deposition. Considering that TGF-ß1 is the master regulator of fibrosis, we further validated at the molecular level that, compared to middle- and late-stage intervention with DDD, early-stage intervention with DDD could significantly decrease the expression levels of factors related to the activated TGF-ß1/Smad signalling pathway, as well as the expression levels of downstream effectors including CTGF, MMP and TIMP family proteins, which were directly involved in ECM remodelling. Therefore, early-stage intervention with DDD can reduce macrovascular fibrosis and prevent diabetic macroangiopathy.
