Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, so there is an urgent need to suppress its development at early stage. Shenkang pills (SKP) are a hospital prescription selected and optimized from effective traditional Chinese medicinal formulas for clinical treatment of DN. In the present study, liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-Q-TOF-MS) and total contents qualification were applied to generate a quality control standard of SKP. For verifying the therapeutic effects of SKP, db/db mice were administered intragastrically with SKP at a human-equivalent dose (1.82 g/kg) for 4 weeks. Moreover, the underlying mechanism of SKP were analyzed by the renal RNA sequencing and network pharmacology. LC-Q-TOF-MS identified 46 compounds in SKP. The total polysaccharide and organic acid content in SKP were 4.60 and 0.11 mg/ml, respectively, while the total flavonoid, saponin, and protein content were 0.25, 0.31, and 0.42 mg/ml, respectively. Treatment of SKP significantly reduced fasting blood glucose, improved renal function, and ameliorated glomerulosclerosis and focal foot processes effacement in db/db mice. In addition, SKP protected podocytes from injury by increasing nephrin and podocin expression. Furthermore, transcriptome analyses revealed that 430 and 288 genes were up and down-regulated in mice treated with SKP, relative to untreated controls. Gene ontology enrichment analysis revealed that the differentially expressed genes mainly involved in modulation of cell division and chromosome segregation. Weighted gene co-expression network analysis and network pharmacology analysis indicated that aurora kinase B (AURKB), Rac GTPase activating protein 1 (RacGAP1) and SHC binding, and spindle associated 1 (shcbp1) might be the core targets of SKP. This protein and Ras homolog family member A (RhoA) were found overexpression in db/db mice, but significantly decreased with SKP treatment. We conclude that SKP can effectively treat early-stage DN and improve renal podocyte dysfunction. The mechanism may involve down-regulation of the AURKB/RacGAP1/RhoA pathway.
Highlights
Diabetic nephropathy (DN) is a common chronic complication of diabetes mellitus (Gross et al, 2005)
Increased urinary protein is a sign of early-stage of DN, which correlates with impaired glomerular filtration, and the renal function damage progression (Mogensen et al, 1983)
Ras homolog family member A (RhoA) is a molecular switch that controls a series of signal transduction pathways, including extracellular signal-regulated kinase (ERK), and Wnt/βcatenin (Krepinsky, 2003; Kim et al, 2018)
Summary
Diabetic nephropathy (DN) is a common chronic complication of diabetes mellitus (Gross et al, 2005). RhoA is a member of the Rho family of small GTPases (Rho GTPases), which have important roles in actin cytoskeleton regulation (Matsuda et al, 2021). It is well-documented that excessive activation of RhoA and its downstream Rho-Kinase, induces glomerulosclerosis by causing podocytes dysfunction, renal epithelial-mesenchymal transition, and matrix upregulation in mesangial cells (Patel et al, 2005; Peng et al, 2008; Zhu et al, 2011). RhoA is a molecular switch that controls a series of signal transduction pathways, including ERK, and Wnt/βcatenin (Krepinsky, 2003; Kim et al, 2018). AURKB has been studied extensively in the context of oncology; its role in DN remains unknown
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