Sweet Taste Receptors Mediated ROS-NLRP3 Inflammasome Signaling Activation: Implications for Diabetic Nephropathy.

Luping Zhou,Yong Xu,Yan Liu,Wei Huang,Jingya Ding,Man Guo,Ludan Qin,Youhua Xu,Ting Zhang,Chenlin Gao,Zihao Xu,Yang Long

doi:10.1155/2018/7078214

Abstract

Previous studies demonstrated that ROS-NLRP3 inflammasome signaling activation was involved in the pathogenesis of diabetic nephropathy (DN). Recent research has shown that sweet taste receptors (STRs) are important sentinels of innate immunity. Whether high glucose primes ROS-NLRP3 inflammasome signaling via STRs is unclear. In this study, diabetic mouse model was induced by streptozotocin (STZ) in vivo; mouse glomerular mesangial cells (GMCs) and human proximal tubular cells were stimulated by high glucose (10, 20, and 30 mmol/L) in vitro; STR inhibitor lactisole was used as an intervention reagent to evaluate the role and mechanism of the STRs in the pathogenesis of DN. Our results showed that the expression of STRs and associated signaling components (Gα-gustducin, PLCβ2, and TRPM5) was obviously downregulated under the condition of diabetes in vivo and in vitro. Furthermore, lactisole significantly mitigated the production of intracellular ROS and reversed the high glucose-induced decrease of Ca2+ and the activation of NLRP3 inflammasome signaling in vitro (p < 0.05). These combined results support the hypothesis that STRs could be involved in the activation of ROS-NLRP3 inflammasome signaling in the pathogenesis of DN, suggesting that STRs may act as new therapeutic targets of DN.

Highlights

Oxidative stress and persistent microinflammatory state in circulatory and renal tissues play a key role in the development and progression of diabetic nephropathy (DN) [1, 2]
We reported previously that high glucose and lipopolysaccharide activate ROS-TXNIP-NOD-like receptor pyrin 3 (NLRP3) inflammasome signaling in glomerular mesangial cells (GMCs), but ROS inhibitor N-acetylcysteine (NAC) could not completely inhibit the activation of NLRP3 inflammasome induced by high glucose, suggesting that there may be other pathways by which high glucose primes ROS-NLRP3 inflammasome signaling [16]
Urinary ACR novel mechanism of blood pressure regulation and kidney glucose handling [20], here, our research indicated that sweet taste receptors (STRs) and associated signaling components were expressed in kidney in vivo and in vitro; we characterize for the first time that compared with the NC group, these signaling molecule expressions were downregulated in

Summary

Introduction

Oxidative stress and persistent microinflammatory state in circulatory and renal tissues play a key role in the development and progression of diabetic nephropathy (DN) [1, 2]. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is an intracellular platform that recruits the adaptor moleculeapoptosis-associated speck-like protein (ASC) by pyrin domain, and ASC hydrolyzes procaspase-1, and active caspase-1 cleaves pro-IL-1β into its mature form in response to “danger” signals [3]. The pharmacological targeting of the oxygen species- (ROS-) NLRP3-mediated inflammatory response may help with the design of a new approach to develop therapeutic strategies for preventing the deterioration of kidney injury in the pathogenesis of DN. The mechanism mediating NLRP3 inflammasome activation in DN has not been completely clarified yet [4].

Methods

Results

Conclusion