Abstract
Abnormal and excessive growth of mesangial cells is important in the pathophysiologic processes of diabetes-associated interstitial fibrosis and glomerulosclerosis, leading to diabetic nephropathy, which eventually turns into end-stage renal disease. Sauchinone, a biologically-active lignan isolated from aerial parts of Saururus chinensis, has anti-inflammatory and anti-viral activities effects on various cell types. However, there are no studies reporting the effects of sauchinone on diabetic nephropathy. The present study aims to investigate the role of sauchinone in mesangial cell proliferation and fibrosis induced by angiotensin II, as well as the underlying mechanisms of these processes. Human renal mesangial cells were induced by angiotensin II (AngII, 10 μM) in the presence or absence of sauchinone (0.1–1 μM) and incubated for 48 h. In this study, we found that AngII induced mesangial cell proliferation, while treatment with sauchinone inhibited the cell proliferation in a dose-dependent manner. Pre-treatment with sauchinone induced down-regulation of cyclins/CDKs and up-regulation of CDK inhibitor, p21, and p27kip1 expression. In addition, AngII-enhanced expression of fibrosis biomarkers such as fibronectin, collagen IV, and connective tissue growth factor (CTGF), which was markedly attenuated by sauchinone. Sauchinone also decreased AngII-induced TGF-β1 and Smad-2, Smad-3, and Smad-4 expression. This study further revealed that sauchinone ameliorated AngII-induced mesangial inflammation through disturbing activation of inflammatory factors, and NLRP3 inflammasome, which is composed of the NLRP3 protein, procaspase-1, and apoptosis-associated speck-like protein containing a CARD (ASC). Moreover, pretreatment of sauchinone inhibited NF-κB translocation and ROS production in AngII-exposed mesangial cells. These data suggest that sauchinone has a protective effect on renal proliferation, fibrosis and inflammation. Therefore, sauchinone might be a potential pharmacological agent in prevention of AngII-induced renal damage leading to diabetic nephropathy.
Highlights
Diabetic nephropathy (DN) is a representative complication of diabetes and is a leading cause of end-stage renal disease [1]
Numerous studies have demonstrated that the intrarenal renin–angiotensin system plays an have demonstrated that the intrarenal renin–angiotensin system plays an important role in diabetic nephropathy
This research proved for the first time that sauchinone isolated from the aerial part of S. chinensis improves diabetic nephropathy by alleviating Angiotensin II (AngII)-induced glomerular fibrosis and inflammation in human kidney mesangial cells
Summary
Diabetic nephropathy (DN) is a representative complication of diabetes and is a leading cause of end-stage renal disease [1]. DN is characterized by aberrant alterations such as glomerular mesangial cell proliferation, hypertrophy, and extracellular matrix (ECM) accumulation in the glomeruli [2,3]. The first and most prominent glomerular lesion of diabetic nephropathy is mesangial expansion concurrently accompanying mesangial hyperplasia called diabetic glomerulosclerosis. An imbalance in the control of mesangial cell proliferation appears to play an early and crucial role in progressive glomerular injury that leads to glomerular sclerosis [4]. Inhibiting the proliferation of mesangial cells and the accumulation of ECM can be applied as a practical approach for treating or relieving DN [6]. The underlying mechanism is still unsatisfactory, and there is no effective therapeutic treatment drug
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