Quercetin and Allopurinol Ameliorate Kidney Injury in STZ-Treated Rats with Regulation of Renal NLRP3 Inflammasome Activation and Lipid Accumulation

Acute kidney injury (AKI) is a critical clinical disease characterized by an acute decrease in renal function. Long non-coding RNAs (LncRNAs) are important in AKI. This study aimed to explore the mechanism of lncRNA Kcnq1ot1 in AKI by sponging microRNA (miR)-204-5p as a competitive endogenous RNA (ceRNA). AKI mouse model and hypoxia/reoxygenation (H/R) model of human kidney (HK) cells were established. Kcnq1ot1 expression, cell proliferation, and apoptosis were measured. Binding relations among Kcnq1ot1, miR-204-5p, and NLRP3 were verified. Pathological changes and cell apoptosis were detected. The results showed that Kcnq1ot1 was highly expressed in the AKI model in vivo and in vitro. Kcnq1ot1 knockdown promoted cell proliferation and prevented apoptosis and inflammation. Furthermore, Kcnq1ot1 inhibited miR-204-5p expression by competitively binding to miR-204-5p in HK-2 cells. miR-204-5p targeted NLRP3 and NLRP3 overexpression averted the inhibiting effect of miR-204-5p on apoptosis and inflammation in HK-2 cells in vitro. Kcnq1ot1 knockdown in vivo promoted miR-204-5p expression, inhibited NLRP3 inflammasome activation, reduced levels of SCr, BUN, and KIM-1, and thus alleviated AKI and reduced apoptosis. In summary, silencing lncRNA Kcnq1ot1 inhibited AKI by promoting miR-204-5p and inhibiting NLRP3 inflammasome activation.

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A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation

Diabetes Metabolic Syndrome and Obesity Targets and Therapy ◽

10.2147/dmso.s199802 ◽

2019 ◽

Vol Volume 12 ◽

pp. 1297-1309 ◽

Cited By ~ 14

Author(s):

CongXiao Zhang ◽

XinWang Zhu ◽

LuLu Li ◽

TianKui Ma ◽

Mai Shi ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Small Molecule ◽

Nlrp3 Inflammasome ◽

Kidney Injury ◽

Small Molecule Inhibitor ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Molecule Inhibitor

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Empagliflozin Alleviates Diabetic Renal Tubular Lipid Accumulation and NLRP3 Inflammasome Activation Through AGEs-RAGE Pathway

10.21203/rs.3.rs-870754/v1 ◽

2021 ◽

Author(s):

Zheng Liu ◽

Juan Chen ◽

Lili Sun ◽

Jianzhong Li ◽

Hong Sun

Keyword(s):

Er Stress ◽

Nlrp3 Inflammasome ◽

Lipid Accumulation ◽

Cholesterol Metabolism ◽

Basal Diet ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Renal Tubular

Abstract Background: Advanced glycation end products (AGEs) are pathogenic factors of renal tubular lipid accumulation and play a negative role in diabetic kidney disease (DKD). Glucose cotransporter (SGLT) 2 inhibition offers strong renoprotection in the progression of DKD. The aim of the current study was to investigate the effects of empagliflozin (EMPA, a potent and selective SGLT2 inhibitor) on AGEs-induced renal tubular lipid accumulation in both diabetic mice fed with a high-AGEs diet and AGEs-treated cultured human renal proximal tubular epithelial (HK-2) cells. Methods: In vivo, EMPA was used to treat db/db mice fed a high-AGEs diet or an AIN-76 basal diet. In an in vitro study, HK-2 cells were treated with AGEs-bovine serum albumin (BSA) and/or EMPA. Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) translocation was detected by confocal microscopy. Results: EMPA reduced tubular lipid droplets and intracellular cholesterol content, as well as the expression of proteins involved in the synthesis and absorption of cholesterol in the kidneys of basal diet-fed db/db mice, high-AGEs diet-fed db/db mice and AGEs-BSA-treated HK-2 cells. AGEs-BSA loading promoted the formation of SCAP-SREBP-2 complexes and enhanced the transport of the complexes to the Golgi, but these effects were markedly inhibited by EMPA in HK-2 cells. EMPA reduced renal inflammation both in basal diet-fed db/db mice and high-AGEs diet-fed db/db mice, and suppressed NLRP3 inflammasome activation in AGEs-BSA-treated HK-2 cells. In addition, EMPA reduced the serum AGEs level in vivo and inhibited renal tubular endoplasmic reticulum (ER) stress and receptor of AGEs (RAGE) expression both in vivo and in vitro. Conclusions: EMPA attenuated AGEs synthesis and inhibited the AGEs-RAGE signaling pathway, thereby suppressing ER stress and inhibiting abnormal cholesterol metabolism and release of inflammatory cytokines, thus alleviating renal tubular lipid accumulation and inflammation.

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