Abstract
Acute kidney injury (AKI) is responsible for significant mortality among hospitalized patients that is especially troubling aged people. An effective self-made Chinese medicine formula, Xiaoyu Xiezhuo Drink (XXD), displayed therapeutic effects on AKI. However, the compositions and underlying mechanisms of XXD remain to be elucidated. In this study, we used the ultra-high-performance liquid chromatography method coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) to investigate the chemical components in XXD. Then, the absorbable components of XXD were identified based on the five principles and inputted into the SwissTargetPrediction and STITCH databases to identify the drug targets. AKI-related targets were collected from the GenCLiP 3, GeneCards, and DisGeNET databases. The crossover genes of XXD and AKI were identified for functional enrichment analysis. The protein-protein interaction (PPI) network of crossover genes was constructed, followed by the identification of hub genes. Subsequently, the effects and potential mechanisms of XXD on AKI predicted by the network pharmacology and bioinformatics analyses were experimentally validated in ischemia-reperfusion (I/R) injury-induced AKI aged mouse models. A total of 122 components in XXD were obtained; among them, 58 components were found that could be absorbed in the blood. There were 800 potential drug targets predicted from the 58 absorbable components in AKI which shared 36 crossover genes with AKI-related targets. The results of functional enrichment analysis indicated that crossover genes mostly associated with the response to oxidative stress and the HIF1 signaling pathway. In the PPI network analysis, 12 hub genes were identified, including ALB, IL-6, TNF, TP53, VEGFA, PTGS2, TLR4, NOS3, EGFR, PPARG, HIF1A, and HMOX1. In AKI aged mice, XXD prominently alleviated I/R injury-induced renal dysfunction, abnormal renal pathological changes, and cellular senescence, inflammation, and oxidative damage with a reduction in the expression level of the inflammatory mediator, α-SMA, collagen-1, F4/80, TP53, VEGFA, PTGS2, TLR4, NOS3, EGFR, PPARG, HIF1A, ICAM-1, TGF-β1, Smad3, and p-Smad3 and an increase of nephridial tissue p-H3, Ki67, HMOX1, MMP-9, and Smad7 levels. In summary, our findings suggest that XXD has renoprotective effects against AKI in aged mice via inhibiting the TGF-β1/Smad3 and HIF1 signaling pathways.
Highlights
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a serious clinical disease characterized by a rapid increase in serum creatinine and a rapid decline in glomerular filtration rate (GFR) [1, 2]
The expression of phosphohistone H3 (p-H3) was during the M phase of the cell cycle, and we found that the levels of p-H3 were obviously increased in the high-dose Xiaoyu Xiezhuo Drink (XXD) group compared with model mice
The pharmacological mechanism of XXD to ameliorate ischemic AKI was explored with the combination of network pharmacology prediction and experimental validation
Summary
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a serious clinical disease characterized by a rapid increase in serum creatinine and a rapid decline in glomerular filtration rate (GFR) [1, 2]. Because of an aging population, it can be seen in up to 7% of hospital admissions and 30% of ICU admissions [3]. It has been demonstrated that AKI leads to the accumulation of water, sodium, several electrolyte disturbances, renal fibrosis, and, eventually, chronic kidney disease (CKD) [3, 4]. The long-term prognosis of AKI, especially in the elderly, is not optimistic. A higher incidence of AKI was observed in older adults [5, 6].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
