Abstract
Chronic glomerulonephritis (CGN) is one of the major causes of end-stage kidney disease. Zhen-wu-tang (ZWT), as a famous Chinese herbal prescription, is widely used in China for CGN therapy in clinic. However, the mechanism of ZWT in CGN has not been fully understood. The present study explored the therapeutic effect and the underlying mechanism of ZWT on mitochondrial function in cationic bovine serum albumin (C-BSA)-induced CGN model rats and tumor necrosis factor (TNF-α)-damaged mouse podocytes. The renal functions were measured by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathological changes and ultrastructure of kidney tissues were evaluated by periodic acid-Schiff (PAS) staining and transmission electron microscopy. The levels of antioxidases, including mitochondrial catalase (CAT), superoxide dismutase 2 (SOD2), and peroxiredoxin 3 (PRDX3), in CGN rats were examined by real-time PCR. The mitochondrial functions of podocytes were measured by ATP concentration, mitochondrial membrane potential (MMP), and mitochondrial ROS (mtROS). For mitophagy level detection, the expressions of mitophagy-related proteins, including LC3, p62, heat shock protein 60 (HSP60), and translocase of outer mitochondrial membrane 20 (TOMM20), were measured by Western blot, as the colocation of LC3 and mitochondrial marker COX IV were evaluated by immunofluorescence. Our results manifested that ZWT ameliorated CGN model rats by a remarkable decrease in Scr and BUN, inhibition of mesangial matrix proliferation, protection against foot processes fusion, and basement membrane thickening. More importantly, ZWT protected against mitochondrial dysfunction by increasing the expressions of CAT, SOD2, and PRDX3 in CGN model rats, increased ATP content and MMP in podocytes, and decreased excessive mtROS. Furthermore, ZWT induced mitophagy in CGN through increasing the expression of LC3, and decreasing p62, HSP60, TOMM20, and ZWT also enhanced the colocation of LC3 to the mitochondria. We found that ZWT inhibited the PI3K/AKT/mTOR pathway, which could be disturbed by PI3K inhibitor LY294002 and agonist insulin-like growth factor 1. Moreover, ZWT reversed the inhibition of the AMPK pathway in CGN. Overall, ZWT ameliorated renal mitochondrial dysfunction probably by inducing mitophagy via the PI3K/AKT/mTOR and AMPK pathways.
Highlights
In 2017, 1.2 million people died from chronic kidney disease (CKD), and the global all-age mortality rate of CKD increased by 41.5% within the last 28 years (Global, 2020)
We found that ZWT protected kidney injury in Chronic glomerulonephritis (CGN) model rats
The mechanisms of ZWT above is related to inducing mitophagy through the phosphatidylinositol 3-kinase (PI3K)/AKT/Mammalian target of rapamycin (mTOR) and AMPK pathways
Summary
In 2017, 1.2 million people died from chronic kidney disease (CKD), and the global all-age mortality rate of CKD increased by 41.5% within the last 28 years (Global, 2020). Chronic glomerulonephritis (CGN) leads to about 20% of CKD, with clinical presentations of proteinuria, hematuria, edema, and hypertension (Floege and Amann, 2016). CGN is the most frequent cause of end-stage renal disease (ESRD) in some developing countries (Chadban and Atkins, 2005). In addition to supportive therapy, immunosuppressive agents are widely used in the management of CGN patients. Many immunosuppressive agents have a narrow therapeutic window and need close monitoring to balance the risk and benefits (Jefferson, 2018). There is no effective treatment that can prevent CGN patients from developing ESRD (Zhang and Zuo, 2016). It is of great importance to clarify the pathogenesis of CGN, which will help us improve the therapeutic effect of CGN and the prognosis of patients
Sign-in/Register to view highlights & summary 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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
