Abstract
Diabetic kidney disease (DKD) is one of the microvascular complications of diabetes mellitus and a major cause of end-stage renal disease with limited treatment options. Wogonin is a flavonoid derived from the root of Scutellaria baicalensis Georgi, which has shown a potent renoprotective effect. But the mechanisms of action in DKD are not fully elucidated. In this study, we investigated the effects of wogonin on glomerular podocytes in DKD using mouse podocyte clone 5 (MPC5) cells and diabetic mice model. MPC5 cells were treated with high glucose (30 mM). We showed that wogonin (4, 8, 16 μM) dose-dependently alleviated high glucose (HG)-induced MPC5 cell damage, accompanied by increased expression of WT-1, nephrin, and podocin proteins, and decreased expression of TNF-α, MCP-1, IL-1β as well as phosphorylated p65. Furthermore, wogonin treatment significantly inhibited HG-induced apoptosis in MPC5 cells. Wogonin reversed HG-suppressed autophagy in MPC5 cells, evidenced by increased ATG7, LC3-II, and Beclin-1 protein, and decreased p62 protein. We demonstrated that wogonin directly bound to Bcl-2 in MPC5 cells. In HG-treated MPC5 cells, knockdown of Bcl-2 abolished the beneficial effects of wogonin, whereas overexpression of Bcl-2 mimicked the protective effects of wogonin. Interestingly, we found that the expression of Bcl-2 was significantly decreased in biopsy renal tissue of diabetic nephropathy patients. In vivo experiments were conducted in STZ-induced diabetic mice, which were administered wogonin (10, 20, 40 mg · kg−1 · d−1, i.g.) every other day for 12 weeks. We showed that wogonin administration significantly alleviated albuminuria, histopathological lesions, and p65 NF-κB-mediated renal inflammatory response. Wogonin administration dose-dependently inhibited podocyte apoptosis and promoted podocyte autophagy in STZ-induced diabetic mice. This study for the first time demonstrates a novel action of wogonin in mitigating glomerulopathy and podocytes injury by regulating Bcl-2-mediated crosstalk between autophagy and apoptosis. Wogonin may be a potential therapeutic drug against DKD.
Highlights
Diabetic kidney disease (DKD) remains a growing health concern and is characterized by chronic inflammation, hemodynamic changes, and metabolic dysfunction [1, 2]
Wogonin promotes high glucose (HG)-suppressed autophagy in mouse podocyte clone 5 (MPC5) cells Western blot analysis showed that wogonin treatment increased the ATG7, LC3-II, and Beclin-1 protein levels that were downregulated due to HG stimulation
Wogonin alleviates HG-induced apoptosis in MPC5 cells Wogonin treatment caused a decrease in the protein levels of cleaved caspase-3, and Bax and an increase in Bcl-2 protein levels in MPC5 cells (Fig. 3a)
Summary
Diabetic kidney disease (DKD) remains a growing health concern and is characterized by chronic inflammation, hemodynamic changes, and metabolic dysfunction [1, 2]. The early pathological changes in DKD mainly include podocyte injury, shed, and apoptosis, while the surviving podocytes show compensatory hypertrophy and podocyte fusion [3, 4]. Prevention and control of DKD in clinical practice mainly includes early diagnosis, improved control of blood glucose, and the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockades [7]. These treatments delay the progression of DKD to a certain extent, they cannot prevent progression to end-stage renal disease. The specific molecular mechanism and effective treatment of DKD need to be further explored
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have