Qigui-Yishen decoction delays renal fibrosis in mice with chronic kidney disease by regulating TM and PAI-1

Objective: To explore the mechanism of Qigui-Yishen decoction in delaying renal fibrosis in mice by regulating thrombin regulatory protein (Thrombomodulin, TM) and plasminogen activator inhibitor-1 (PAI-1) based on network pharmacology. Methods: The active ingredients of Qigui Yishen decoction and their target molecules associated with chronic kidney disease (CKD) were retrieved from websites and databases, sorted out, and screened, and the possible targets of Qigui Yishen decoction for reducing CKD renal fibrosis were predicted and analyzed. Forty Institute of Cancer research (ICR) rats were used to establish a unilateral ureteral obstruction (UUO) model, and divided into several groups: sham operation group, model group, high concentration decoction group (1 g/mL), low concentration decoction group (0.46 g/mL), and benazepril group (0.1 g/mL). At the end of the experiment, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected. Masson staining was used to observe changes in the renal interstitial fibrosis index. Immunohistochemistry and western blot were used to detect the expressions of TM, PAI-1, transforming growth factor-beta 1 (TGF-beta 1) and collagen I (Col I) in kidney tissues, and the differences between groups were compared. Results: Qigui Yishen decoction contains 42 effective ingredients such as sitosterol, mannitol, and quercetin, with 662 drug targets and 16154 disease targets. Analysis revealed 570 potential targets, including TM4SF19, PAIP1, TGF-beta 1, and Col I-AI. Compared to the sham operation group, all treatment groups exhibited increased Scr and BUN levels (P<0.05) and enhanced renal interstitial fibrosis (P<0.05) after UUO model establishment. Moreover, immunohistochemical results showed significant increases in PAI-1, TGF-beta 1, and Col I (all P<0.05), and a significant decrease in TM expression (P<0.05). Compared to the model group, the high concentration decoction group, low concentration decoction group and benazepril group had no significant difference in Scr and BUN values (P>0.05), but the renal interstitial fibrosis index was lower (P<0.05). Also, the relative expressions of PAI-1, TGF-beta 1 and Col I in the kidney tissue of mice were decreased, while the relative expression of TM was increased (P<0.05). Conclusion: Qigi Yishen decoction has the characteristics of multiple components and multiple targets, and can play a role in delaying renal fibrosis by regulating the expression of PAI-1, TGF-beta 1, Col I, and TM.