Bu-Shen-Huo-Xue Decoction Ameliorates Diabetic Nephropathy by Inhibiting Rac1/PAK1/p38MAPK Signaling Pathway in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Weisong Wang; Hongping Long; Wei Huang; Ting Zhang; Lihua Xie; Cheng Chen; Jianhe Liu; Dan Xiong; Wei Hu

doi:10.3389/fphar.2020.587663

Bu-Shen-Huo-Xue Decoction Ameliorates Diabetic Nephropathy by Inhibiting Rac1/PAK1/p38MAPK Signaling Pathway in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Front Pharmacol. 2020 Dec 3:11:587663. doi: 10.3389/fphar.2020.587663. eCollection 2020.

Authors

Weisong Wang¹, Hongping Long², Wei Huang¹, Ting Zhang¹, Lihua Xie¹, Cheng Chen¹, Jianhe Liu³, Dan Xiong⁴, Wei Hu⁵

Affiliations

¹ Graduate School, Hunan University of Chinese Medicine, Changsha, China.
² Experiment Center of Medical Innovation, The First Hospital of Hunan University of Chinese Medicine, Changsha, China.
³ Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China.
⁴ Department of Nephrology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China.
⁵ Department of Endocrinology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China.

Abstract

Diabetic nephropathy (DN), a leading cause of end-stage renal disease, is associated with high morbidity and mortality rates worldwide and the development of new drugs to treat DN is urgently required. Bu-Shen-Huo-Xue (BSHX) decoction is a traditional Chinese herbal formula, made according to traditional Chinese medicine (TCM) theory, and has been used clinically to treat DN. In the present study, we established a high-fat diet/streptozotocin-induced diabetic mouse model and treated the mice with BSHX decoction to verify its therapeutic effects in vivo. Ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to analyze the chemical composition and active compounds of BSHX decoction. Markers of podocyte epithelial-mesenchymal transition and the Rac1/PAK1/p38MAPK signaling pathway were evaluated to investigate the mechanism underlying function of BSHX decoction. BSHX decoction effectively alleviated diabetic symptoms, according to analysis of the renal function indicators, serum creatinine, blood urea nitrogen, serum uric acid, and urinary albumin excretion rate, as well as renal histopathology and ultrastructural pathology of DN mice. We identified 67 compounds, including 20 likely active compounds, in BSHX decoction. The podocyte markers, nephrin and podocin, were down-regulated, while the mesenchymal markers, α-SMA and FSP-1, were up-regulated in DN mouse kidney; however, the changes in these markers were reversed on treatment with BSHX decoction. GTP-Rac1 was markedly overexpressed in DN mice and its levels were significantly decreased in response to BSHX decoction. Similarly, levels of p-PAK1 and p-p38MAPK which indicate Rac1 activation, were reduced on treatment with BSHX decoction. Together, our data demonstrated that BSHX decoction ameliorated renal function and podocyte epithelial-mesenchymal transition via inhibiting Rac1/PAK1/p38MAPK signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Further, we generated a quality control standard and numerous potential active compounds from BSHX decoction for DN.

Keywords: Bu-Shen-Huo-Xue decoction; PAK1; Rac1; diabetic nephropathy; p38MAPK; podocyte epithelial-mesenchymal transition.