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Three signaling pathways of the unfolded protein response. Materials provided by Servier Medical Art (smart.servier.com).
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Diabetic nephropathy (DN), a prevalent microvascular complication of diabetes mellitus, is the primary contributor to end-stage renal disease in developed countries. Existing clinical interventions for DN encompass lifestyle modifications, blood glucose regulation, blood pressure reduction, lipid management, and avoidance of nephrotoxic medications...
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Context 1
... when ER stress is induced, an accumulation of unfolded or misfolded proteins results in the binding to GRP78, causing the disassociation of GRP78 from PERK, IRE1, and ATF6. This disassociation instigates the subsequent induction of downstream signaling pathways ( Figure 2). Among these proteins, PERK plays a pivotal role in the modulation of ER stress. ...
Context 2
... research indicates that curcumin mitigates angiotensin II-induced podocyte damage and apoptosis, partly through ER stress inhibition ( Yu et al., 2020). In vivo studies confirm that curcumin mediates nephroprotective effects in DN rats by suppressing the activation of the ER stress-mediated apoptotic signaling pathways JNK and Notch2/hes1 (Deng et al., 2020). Epigallocatechin-3-gallate (EGCG), the primary bioactive compound in catechins, has demonstrated significant hypotensive, hypolipidemic, anti-diabetic, and nephroprotective activities in previous studies ( Bazyar et al., 2020;Mohan et al., 2020;Zhu et al., 2022). ...
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Citations
Endoplasmic reticulum (ER) stress and chronic sterile inflammation are associated with the pathogenesis of diabetic nephropathy (DN). Catechins are natural polyphenolic compounds found in green tea that possess some health benefits. However, whether (+)-catechin can reduce tubular injury in DN by regulating ER stress and NLRP3-associated inflammation remains uncertain. This study examined the effects of (+)-catechin on streptozotocin (STZ)-induced diabetic mice and on palmitic acid (PA)-treated HK-2 cells. In vivo, a DN mouse model was generated by injecting STZ. The biochemical indicators of serum and urine, as well as renal histopathology and ultrastructure were analysed. To predict the mechanisms associated with (+)-catechin, network pharmacology and molecular docking were used. Finally, quantitative real-time PCR (qPCR), western blot analysis and immunofluorescence analysis were performed to measure the mRNA and protein expressions of specific targets in the renal tissue of DN mice and PA-treated HK-2 cells to validate the predicted results. (+)-Catechin significantly ameliorated renal function and pathological changes associated with tubular injury by inhibiting ER stress by downregulating of GRP78, PEAK, CHOP, ATF6 and XBP1. In addition, (+)-catechin inhibited renal inflammation by suppressing NLRP3 associated inflammation, which was characterized by the downregulation of NLRP3, ASC, AIM2, Caspase1, IL-1β and IL-18 in DN mice and PA-treated HK-2 cells. Collectively, these findings suggested that (+)-catechin exerted a renoprotective effect against DN by inhibiting ER stress and NLRP3-related inflammation to ameliorate tubular injury, suggesting the therapeutic potential of (+)-catechin.
