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

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.

“Qi Nan” agarwood restores podocyte autophagy in diabetic kidney disease by targeting EGFR signaling pathway

“…There is a significant body of literature demonstrating an increased interest in herbal products, driven by the recognition that multi-ingredient formulations offer enhanced efficacy for managing complex diseases [ 38 , 39 ]. Traditional Chinese Medicine has shown remarkable effectiveness in alleviating clinical symptoms, slowing the progression of DKD, enhancing renal function, and improving patients' quality of life.…”

Recent Advances in Clinical Diagnosis and Pharmacotherapy Options of Membranous Nephropathy

“…Natural products or traditional Chinese medicines have been long used in patients and considered an alternative therapeutic strategy for prevention and treatment of glomerular-associated diseases including MN ( Feng et al, 2020 ), glomerulonephritis ( Gianassi et al, 2019 ; Wang et al, 2021 ), diabetes ( Chen et al, 2020b ; Wang et al, 2020b ; Fang et al, 2021 ; Su et al, 2021 ; He et al, 2022 ), and diabetic nephropathy ( Li et al, 2020a ; Yang et al, 2020 ; Wang, 2021 ; Xuan et al, 2021 ; Yang and Wu, 2021 ; Zhou et al, 2021 ; Liu et al, 2022 ). Earlier finding have demonstrated that a 77-year-old woman with IMN was treated by Astragalus membranaceus and achieved clinical remission without using immunosuppressive therapy ( Ahmed et al, 2007 ).…”

Traditional Chinese Medicine in Treating Primary Podocytosis: From Fundamental Science to Clinical Research

“…Bu-Shen-Huo-Xue Decoction upregulates the podocyte markers nephrin and podocin in high-fat diet/STZ-induced diabetic mice and downregulates mesenchymal markers. α-SMA and fibroblast-specific protein 1 are expressed to improve renal function and inhibit podocyte EMT ( Wang et al, 2020 ). Rhodiola can increase the expression levels of nephrin and podocin and protect podocytes by regulating SIRT1/PGC-1α-mediated mitochondrial bioactivity and inhibiting the β-catenin signaling pathway ( Huang et al, 2019 ; Xue et al, 2019 ).…”