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

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.

Role of Inflammasomes in Kidney Diseases via Both Canonical and Non-canonical Pathways

“…ROS signal pathway has been shown to be closely related to the DN (Qiu and Tang, 2016). Zhou et al (2018) proved that high glucose can induce the activation of ROS-meditated activation of the NLRP3 inflammasome. Xu et al (2018) showed that TXNIP can induce the oxidative stress response in glomerular mesangial cells, while Tan et al (2015) found that TXNIP inhibited tubule-interstitial compartment from acting as an important meditator in the process of tubule-interstitial fibrosis in DN.…”

Pattern recognition receptor‐mediated inflammation in diabetic vascular complications

“…135 HG and AGEs induce the production of ROS, 139 which activates thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome in glomerular mesangial cells, 136 podocytes, 139 and proximal tubular cells. 137 The most convincing evidence illustrating the role of NLRs in diabetic nephropathy comes from NLRP3 knockout mice which fail to develop diabetes-induced kidney abnormalities. 141 Receiver operating characteristic analysis revealed that the relative expression of NLRP3 mRNA is a useful biomarker of nephropathy in T2DM patients.…”

“…In long-standing diabetes, cardiac and vascular injury is, to a large extent, caused by HG-activated NLRP3 inflammasome, which drives inflammatory responses by not only inducing cytokines, such as IL-1β and IL-18, but also causing pyroptosis. 137,157,158 Hyperglycemia has been shown to activate the NLRP3 inflammasome in various cell populations of the heart, including cardiomyocytes and cardiofibroblasts, 157,[159][160][161] leading to cardiac inflammation, fibrosis, and apoptosis. 162,163 HG-induced activation of NLRP3 can also be regulated by Syk/JNK and TLR4/ NF-κB pathways.…”

Non-Nutritive Sweeteners and Their Implications on the Development of Metabolic Syndrome

“…Welcome reviewed recent evidence to demonstrate that the sweet taste receptor heterodimer T1R2/T1R3 plays a crucial role in cognitive functioning, suggesting that dysfunctions in sweet taste receptor signaling may underlie cognitive impairment in some brain pathologies [122]. Dysfunctions in sweet taste receptor signaling were also associated with inflammatory response pathway [123]. The study showed that sweet taste receptors function as pivotal immune sentinels, revealing the downregulation of the key components of the taste signaling cascades such as α-gustducin, phospholipase C β2, and monovalent selective cation channel TRPM5, contributing to cognitive impairment [123].…”

“…Dysfunctions in sweet taste receptor signaling were also associated with inflammatory response pathway [123]. The study showed that sweet taste receptors function as pivotal immune sentinels, revealing the downregulation of the key components of the taste signaling cascades such as α-gustducin, phospholipase C β2, and monovalent selective cation channel TRPM5, contributing to cognitive impairment [123].…”