TLR7 mediates increased vulnerability to ischemic acute kidney injury in diabetes

Abstract

SUMMARY OBJECTIVE Diabetes is a risk factor for acute kidney injury (AKI). However, its mechanism of pathogenesis has not been elucidated. The aim of the study was to investigate the role of inflammation and the toll-like receptor 7 (TLR7) in ischemic AKI for diabetes. METHODS A high glucose hypoxia-reoxygenation model of human renal tubular epithelial (HK-2) cells was used to generate AKI induced by ischemia-reperfusion in diabetes. The activity of cells was measured by CCK-8 assay and LDH activity. Inflammatory cytokines were assessed by ELISA. TLR7, MyD88, and NF-κB expressions were examined by western blotting. Apoptosis was evaluated by flow cytometry. RESULTS The high glucose group and low glucose group were subjected to hypoxia-reoxygenation. The low glucose group developed only mild cell damage, apoptosis, and inflammatory response. In contrast, an equivalent hypoxia-reoxygenation injury provoked severe cell damage, apoptosis, and inflammatory response in the high glucose group. Expression of TLR7 and its related proteins were measured in the high glucose group before and after hypoxia-reoxygenation. The high glucose group exhibited more significant increases in TLR7 expression following hypoxia-reoxygenation than the low glucose group. In addition, the expression of TLR7 and its related proteins after hypoxia-reoxygenation were higher in the high glucose group than in the low glucose group. Inhibition of TLR7 provides significant protection against ischemic injury in diabetes. CONCLUSION Our results suggest that diabetes increases the vulnerability to ischemia-induced renal injury. This increased vulnerability originates from a heightened inflammatory response involving the TLR7 signal transduction pathway.

Identification of biomarkers and pathways for focal segmental glomerulosclerosis using next generation sequencing data and bioinformatics analysis

“…The GO [64], PLA2G6 [65], RGS2 [66], GPS2 [67], SOX5 [68], GLUL (glutamate-ammonia ligase) [69], RYK (receptor like tyrosine kinase) [70], NFKBIA (NFKB inhibitor alpha) [71], LGR4 [102], ITGAL (integrin subunit alpha L) [103], CD27 [104], JAK3 [105], CCR5 [106], FCN1 [107], IL1RN [108], CX3CR1 [109], PDCD1 [110], TRPM2 [111], PLEK (pleckstrin) [112], CD101 [113], TNF (tumor necrosis factor) [114], CD48 [115], ALOX5 [116], TLR7 [117], CCL3 [118], C2 [119], TNFRSF1B [120], CCR2 [121], PLA2G7 [122], TH (tyrosine hydroxylase) [123], WNT7A [124], ADRB3 [125], GPBAR1 [126], SLC6A20 [127], FUT2 [128], ANK1 [129], NOS3 [130], APLNR (apelin receptor) [131], COMP (cartilage oligomeric matrix protein) [132], RETN (resistin) [133], NMU (neuromedin U) [134], S100B [135], IGFBP1 [136], COL1A1 [137], HBB (hemoglobin subunit beta) [138] and PLAC8 [139] genes plays important regulatory roles in diabetes mellitus. Various genes such as PDK4 [140], ALB (albumin) [141], EGR1 [142], RYR3 [48], CYP27B1 [143], GATA6 [144], NR4A3 [145], TET2…”

Acute kidney injury in diabetes mellitus: Epidemiology, diagnostic, and therapeutic concepts

“…DM increases kidney vulnerability to AKI by enhancing the production of inflammatory cytokines such as IL‐6 and TNF‐α and the expression of TLR7 in kidney tubular epithelial cells, compared to non‐DM AKI. Inhibition of TLR7 reduces inflammation response, cell apoptosis, and viability of AKI in DM 147 . In vitro, under high glucose and hypoxia stresses, the knockdown of TLR7 reduces apoptosis and increases cell viability by downregulating MyD88 and NF‐κB.…”

“…Inhibition of TLR7 reduces inflammation response, cell apoptosis, and viability of AKI in DM. 147 In vitro, under high glucose and hypoxia stresses, the knockdown of TLR7 reduces apoptosis and increases cell viability by downregulating MyD88 and NF-κB. In particular, DM increases AKI susceptibility after acute myocardial infarction by augmented activation of kidney TLR1/ TLR2 and promoted KIM-1 upregulation.…”

“…It is no exaggeration to say that DM increases organ vulnerability to AKI. This increased vulnerability originates from a heightened inflammatory response involving innate immune‐associated cGAS‐STING and TLR signaling pathways 146,147 . As a component of the innate immune system that functions to detect the presence of cytosolic DNA, the cGAS–STING signaling pathway is highly enriched in immune cells in metabolic tissues.…”

“…This increased vulnerability originates from a heightened inflammatory response involving innate immune-associated cGAS-STING and TLR signaling pathways. 146,147 As a component of the innate immune system that functions to detect the presence of cytosolic DNA, the cGAS-STING signaling pathway is highly enriched in immune cells in metabolic tissues. Activation of the cGAS-STING pathway promotes inflammation and creates a hostile microenvironment that causes insulin resistance.…”