Efficacy of Huangkui Capsules in the Treatment of Diabetic Kidney Disease: A Systematic Review and Using Network Pharmacology
Authors: Geng Yunling , Dong Zhaocheng , Wang Ying , Zhang Pingna , Tang Jingyi , Li Ping , Lv Renhe , Liu Yu Ning , Liu Wei Jing 
Published: April 2023

ABSTRACT
Diabetic kidney disease (DKD), a severe and common microvascular complication of diabetes mellitus, has become a major cause of end-stage renal disease. Huangkui capsule (HKC) has been widely used to treat DKD. This meta-analysis aimed to provide high-quality evidence for the clinical application of HKC in DKD. The following databases: China National Knowledge Infrastructure, Wanfang Database, Chongqing VIP, SinoMed, Web of Science, EMBASE, PubMed, and The Cochrane Library, were searched for randomized controlled trials using the search theme: “angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) combined with HKC for treatment of DKD” from their inception dates till August 2022. Studies were selected following our inclusion and exclusion criteria, and we extracted the required data. RevMan 5.3 was used for data statistics and analysis. Based on the main components identified by high performance liquid chromatography, the SwissADME, SwissTargetPrediction, and UniProt databases were used to predict the target genes of HKC. OMIM, DrugBank, GeneCards, and DisGeNet databases were used to predict DKD-related target genes. Venny 2.0 was then used to find the common targets in HKC and DKD. We conducted an HKC-ingredients-targets-DKD network using Cytoscape and a protein-protein interaction (PPI) network using the STRING database. Finally, we performed a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using the DAVID database. Exactly 15 studies were included in this meta-analysis. Compared with the control group using ACEI/ARB only, ACEI/ARB combined with HKC was found to significantly lower the urine albumin excretion rate (UAER; standard mean difference [SMD] = −1.92, 95% confidence interval [CI] [−2.93, −0.92]), 24h urinary total protein (24h-UTP; mean difference [MD] = −0.41, 95% CI [−0.64, −0.18], P = 0.0004), serum creatinine (SCr; SMD = −0.68, 95% CI [−1.02, −0.34]), blood urea nitrogen (BUN; SMD = −0.59, 95% CI [−1.04, 0.14], P = 0.01), total cholesterol (TC; MD = −1.22, 95% CI [−2.04, 0.39], P = 0.004, and triglyceride (TG) levels (MD = −0.54, 95% CI [−0.94, −0.15], P = 0.007). There was no significant difference in low-density lipoprotein cholesterol levels (MD = −0.45, 95% CI [−1.21, 0.31], P = 0.24) and adverse effects (RR = 0.98, 95% CI [0.43, 2.22], P = 0.96) between the two groups. Exactly 127 genes were obtained using network pharmacology and were the common target genes of HKC and DKD. PPI network showed that the key targets are SRC, AKT1, HSP90AA1, PIK3R1, SYK, FYN, ESR1, and F2. GO analysis and KEGG pathway enrichment analysis showed that HKC could alleviate the pathological glomerular changes by inhibiting the activity of the PI3K/Akt signaling pathway. The combination of ACEI/ARB and HKC has a good safety profile and may be effective for the prevention of DKD by reducing UAER, 24h-UTP, TC, and TG levels. Furthermore, HKC may treat DKD primarily by inhibiting the PI3K-Akt signaling pathway, and further experimental studies are required to verify this hypothesis.