Naringenin alleviates hyperglycemia-induced renal toxicity by regulating activating transcription factor 4–C/EBP homologous protein mediated apoptosis

Endoplasmic reticulum (ER) dysfunction plays a prominent role in the pathophysiology of diabetic nephropathy (DN). This study aimed to investigate the novel role of Naringenin (a flavanone mainly found in citrus fruits) in modulating ER stress in hyperglycemic NRK 52E cells and STZ/nicotinamide induced diabetes in Wistar rats. The results demonstrated that Naringenin supplementation downregulated the expression of ER stress marker proteins, including p-PERK, p-eIF2α, XBP1s, ATF4 and CHOP during hyperglycemic renal toxicity in vitro and in vivo. Naringenin abrogated hyperglycemia-induced ultrastructural changes in ER, evidencing its anti-ER stress effects. Interestingly, treatment of Naringenin prevented nuclear translocation of ATF4 and CHOP in hyperglycemic renal cells and diabetic kidneys. Naringenin prevented apoptosis in hyperglycemic renal cells and diabetic kidney tissues by downregulating expression of apoptotic marker proteins. Further, photomicrographs of TEM confirmed anti-apoptotic potential of Naringenin as it prevented membrane blebbing and formation of apoptotic bodies in hyperglycemic renal cells. Naringenin improved glucose tolerance, restored serum insulin level and reduced serum glucose level in diabetic rats evidencing its anti-hyperglycemic effects. Histopathological examination of kidney tissues also confirmed prevention of damage after 28 days of Naringenin treatment in diabetic rats. Additionally, Naringenin diminished oxidative stress and improved antioxidant defense response during hyperglycemic renal toxicity. Taken together, our study revealed a novel role of Naringenin in ameliorating ER stress during hyperglycemic renal toxicity along with prevention of apoptosis, cellular and tissue damage. The findings suggest that prevention of ER stress can be exploited as a novel approach for the management of hyperglycemic nephrotoxicity. Supplementary InformationThe online version contains supplementary material available at 10.1007/s12079-021-00644-0.     

Critical and functional regulation of CHOP (C/EBP homologous protein) through the N-terminal portion

C/EBP homologous protein (CHOP) is an endoplasmic reticulum stress-inducible protein that plays a critical role in the regulation of programmed cell death; however, the regulation of its function has not been well characterized. We have previously demonstrated that CHOP is regulated by the ubiquitin-proteasome system. In this study, during the process of clarifying the mechanism of the degradation of CHOP, we identified a novel regulation domain of CHOP in its N-terminal portion that is involved in various regulations and functions. The CHOP N-terminal domain is necessary not only for protein degradation but also for its transactivity and interaction with p300. In addition, trichostatin A, a histone deacetylase inhibitor, repressed the degradation of CHOP protein via the N-terminal domain. TRB3, a mammalian tribbles homolog that functions as a repressor of CHOP, also interacted with CHOP via the N-terminal portion and significantly blocked the association of p300 with CHOP. These results suggest that the N-terminal portion of CHOP plays a crucial role in its functional regulation and enable us to identify a novel function of TRB3 as an intracellular antagonist of the p300-binding domain of CHOP.