LncRNA SNHG16 regulates RAS and NF-κB pathway-mediated NLRP3 inflammasome activation to aggravate diabetes nephropathy through stabilizing TLR4.

Abstract

LncRNA SNHG16 and Toll-like receptor-4 (TLR4) participate in diabetes nephropathy. This study investigated whether SNHG16 regulates diabetic renal injury (DRI) via TLR4 and its related mechanism. Diabetic mice and high glucose (HG)-induced HRMCs were used to examine the expressions of SNHG16 and TLR4. The SNHG16 expression, cytokines, reactive oxygen species, MDA, SOD, GSH, and fibrosis-related proteins were evaluated in HG-induced HRMCs transfected with sh-NC or sh-SHNG16. RNA immunoprecipitation and RNA pull-down determined the interaction between SNHG16 and EIF4A3 or TLR4 and EIF4A3. We used HG-treated HRMCs or diabetic mice to investigate the roles of TLR4 or SNHG16 in renal injuries. Both SNHG16 and TLR4 were upregulated in diabetic conditions. HG increased serum Scr and BUN, led to significant fibrosis, increased inflammation- and renal fibrosis-related proteins in mice, and increased ROS, MDA, and decreased SOD and GSH in HRMCs. SNHG16 silencing diminished HG-upregulated SNHG16, decreased HG-increased cytokines secretion, ROS, MDA, and fibrosis but increased SOD and GSH. RIP and RNA pull-down confirmed that SNHG16 recruits EIF4A3 to stabilize TLR4 mRNA. TLR4 knockdown alleviated HG-induced renal injuries by suppressing RAS and NF-κB-mediated activation of NLRP3 inflammasomes. SNHG16 knockdown alleviated HG-induced renal injuries in HG-induced HRMCs or diabetic mice. Interestingly, TLR4 overexpression reversed the effects of SNHG16 knockdown. Mechanistically, SNHG16 knockdown alleviated HG-induced renal injuries by suppressing TLR4. SNHG16 accelerated HG-induced renal injuries via recruiting EIF4A3 to enhance the stabilization of TLR4 mRNA. The SNGHG16/ELF4A3/TLR4 axis might be a novel target for treating DRI.