Sauchinone Protects Renal Mesangial Cell Dysfunction against Angiotensin II by Improving Renal Fibrosis and Inflammation

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.

Involvement of Inflammasome Components in Kidney Disease

“…Moreover, Ang II contributes to DN by inducing glomerular mesangial expansion, membrane basement thickening, and extracellular matrix deposition, and it has been implicated in NLRP3 activation [ 240 ]. In line with this, human mesangial cells exposed to Ang II showed upregulation of NLRP3 protein, caspase-1, and ASC, leading to NLRP3 complex activation [ 241 ]. The upregulation of Ang II prompts the stimulation of NOXs via angiotensin receptor 1 (ATR1), causing ROS overproduction and driving NLRP3 activation via ROS.…”

“…In line with this, albumin overload induces the synthesis of chemokines such as ‘regulated upon activation, normal T cell expressed and presumably secreted’ (RANTES) and monocyte chemoattracted protein (MCP-1) through NF-κB, triggering the recruitment of monocytes and T cells mediated by the secretion IL-1β and IL-18. The latter attracts neutrophils and molecules that further generate ROS accumulation [ 241 ]. Albumin is considered a DAMP able to trigger inflammasome priming because the levels of NLRP3 are albumin dose-dependent [ 255 ].…”

Dopamine receptor D2 inhibition alleviates diabetic hepatic stellate cells fibrosis by regulating the TGF‐β1/Smads and NFκB pathways

“…TGF‐β1 is secreted in the reactivation of HSCs during the formation of fibrosis, which can induce the production of collagens, MMPs and fibronectin 30‐32 . In addition, inflammation is closely related to the occurrence of fibrosis, showing that activation of inflammatory factors can promote cell fibrosis 33,34 .…”

Panax Ginseng C.A.Mey. as Medicine: The Potential Use of Panax Ginseng C.A.Mey. as a Remedy for Kidney Protection from a Pharmacological Perspective

“…Glomerular mesangial cells (MCs) are major components of the glomerular mesangium, hold the capillary arteries and connect them with the juxtaglomerular apparatus. More and more evidences are suggesting the abnormal growth of MCs is an early event in various glomerular diseases ( Yoon et al, 2020 ; Wan et al, 2021 ). Targeting glomerular mesangial cells as the research object and screening for suitable drugs to repair the damage caused by oxidative stress and inflammation have important scientific research significance and clinical value.…”