DsbA-L Ameliorates Renal Injury Through the AMPK/NLRP3 Inflammasome Signaling Pathway in Diabetic Nephropathy

Abstract

NLRP3-mediated inflammation is closely related to the pathological progression of diabetic nephropathy (DN). DsbA-L, an antioxidant enzyme, plays a protective role in a variety of diseases by inhibiting ER stress and regulating metabolism. However, the relationship of DsbA-L with inflammation, especially the NLRP3 inflammasome, has not been examined. In this study, we note that activation of the NLRP3 inflammasome and exacerbated fibrosis were observed in the kidneys of diabetic DsbA-L-knockout mice and were accompanied by decreased phosphorylation of AMP-activated protein kinase (AMPK). Moreover, correlation analysis shows that the phosphorylation of AMPK was negatively correlated with NLRP3 expression and tubular damage. In addition, the decreased AMPK phosphorylation and NLRP3 activation induced by high glucose (HG) in HK-2 cells could be alleviated by the overexpression of DsbA-L. Interestingly, the protective effect of DsbA-L was eliminated after treatment with compound C, a well-known AMPK inhibitor. Our findings suggest that DsbA-L inhibits NLRP3 inflammasome activation by promoting the phosphorylation of AMPK.

Identification and validation of P4HB as a novel autophagy-related biomarker in diabetic nephropathy

“…These processes may be associated with various infections and diseases that were inferred from the enrichment analysis of pathways, including influenza A, lipid dysfunction and atherosclerosis, and cancer. Previous studies have also shown that DN was associated with various autophagy-related biological functions ( Yang M. et al, 2021 ; Liu et al, 2022 ). Then, correlation analysis and the PPI network were constructed to further explore the correlation between the DEARG expression.…”

“…Therefore, novel and satisfactory strategies are urgently needed to treat DN. There is growing evidence that multiple biological functions are engaged in the pathogenesis of DN, such as immunity, inflammation, and autophagy ( Yang et al, 2019 ; Yang M. et al, 2021 ; Yu et al, 2021 ; Li et al, 2022 ). In our research, starting from autophagy, for the first time, we identified DEARGs in DN vs. normal human renal tubular interstitial cells by bioinformatics analysis, as well as determined a new autophagy-related biomarker for DN, thus providing novel insights into the tubulointerstitial pathogenesis of DN and contributing to the identification of novel therapeutic targets.…”

lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

“…Inflammation may play a crucial role in the pathophysiology of DN, as evidence is mounting [23][24][25]. Hyperglycemia can stimulate the secretion of inflammatory cytokines, induce apoptosis, and generate numerous reactive oxygen species, resulting in injury to renal tubular epithelial cells [26], renal [27], mesangial cells [28,29], and podocytes [30].…”

A Glimpse of Inflammation and Anti-Inflammation Therapy in Diabetic Kidney Disease

“…Interestingly, AMPK signaling pathway was related to the renal inflammation ( Garcia and Shaw, 2017 ). Previous study by our group showed that DsbA-L could inhibit the activation of NLRP3 by activating AMPK phosphorylation in the kidney of DKD mice, while the expression levels of IL-18 and IL-1β were increased in that of DKD mice treated with compound C (an AMPK inhibitor) ( Yang et al, 2021a ). AMPK also inhibits the expression of inducible nitric oxide synthase (iNOS), thereby inhibiting the activation of NLRP3 inflammasome ( Pilon et al, 2004 ; Liao et al, 2021 ).…”