Atorvastatin prevents glomerular extracellular matrix formation by interfering with the PKC signaling pathway

Abstract

Platelet-activating factor (PAF) promotes glomerular extracellular matrix (ECM) deposition, primarily through activation of the protein kinase C (PKC) pathway. The present study was designed to investigate whether atorvastatin, which mediates a protective effect against glomerular ECM deposition and diabetic neuropathy, may interfere with the PKC-transforming growth factor-β1 (TGF-β1) pathway in a model of human mesangial cells (HMCs) exposed to a high glucose (HG) and lysophosphatidylcholine (LPC) environment. HMCs were divided into three treatment groups: Control, high glucose and lysophosphatidylcholine (HG+LPC), and HG+LPC+atorvastatin. Cells were cultured for 24 h. The levels of the ECM-associated molecules collagen IV (Col IV) and fibronectin (Fn) in the supernatant were detected using an ELISA kit. PKC-β1, TGF-β1 and PAF-receptor gene expression was detected by reverse transcription-quantitative polymerase chain reaction. PKC-β1 and TGF-β1 protein expression was detected by western blotting, and the subcellular localization of PKC-β1 was assessed using immunofluorescence. The results indicated that atorvastatin may reduce the secretion of ECM components (Fn and Col IV) in HMCs in a HG and LPC environment, by inhibiting the increase in PAF secretion and the activation of the PKC-TGF-β1 signaling pathway.

A Novel Approach Based on Metabolomics Coupled With Intestinal Flora Analysis and Network Pharmacology to Explain the Mechanisms of Action of Bekhogainsam Decoction in the Improvement of Symptoms of Streptozotocin-Induced Diabetic Nephropathy in Mice

“…This pathway also regulates the permeability of glomerular endothelial cells and, simultaneously, the synthesis and transformation of extracellular matrix in kidney tissue (Sajan and Farese, 2012;Yang and Zhang, 2015). PKC participates in the injury of glomerular podocytes by activation of the TGF-b1 signaling pathway (Xiao et al, 2018). TGF-b1, one of the most critical fibrogenic factors, increases the synthesis of extracellular matrix (ECM) in the mesangial area of the kidney and accelerates thickening of the glomerular basement membrane, thereby inducing glomerular sclerosis and renal failure.…”

Pathomechanisms of Diabetic Kidney Disease

“…Transforming growth factor β1 (TGF-β1) plays a significant role in the accumulation of GBM and ECM in DKD [45,46] along with heightened activation of PKC [22,47,48]. Inhibition of PKC-α and PKC-β leads to a reduction in the expression of TGF-β1 and connective tissue growth factor (CTGF) in both glomerular endothelial cells and mesangial cells [22,39,40,47,49,50]. Mice with a knockout of Akr1b3 show inhibited PKC activation, resulting in decreased ECM accumulation and glomerular hypertrophy [51].…”

The role of protein kinase C in diabetic microvascular complications

“…PKC activation and the expression of TGF-β1 in mesangial cells and glomerular endothelial cells were increased under treatment with glycated albumin and advanced oxidation protein products (the level of glycated albumin and advanced oxidation protein products are elevated under high glucose, which mimics the alternations in vivo ) ( 62 – 64 ). Inhibition of PKC-α and PKC-β attenuated the expression of TGF-β1 and connective tissue growth factor (CTGF) in glomerular endothelial cells and mesangial cells ( 54 , 55 , 62 , 64 – 66 ). Interactions between other molecules and PKC in terms of ECM protein synthesis and basement thickening have also been explored.…”