Endoplasmic reticulum stress-dependent activation of TRB3-FoxO1 signaling pathway exacerbates hyperglycemic nephrotoxicity: Protection accorded by Naringenin

• Published in: European journal of pharmacology 2022-02, Vol.917, p.174745, Article 174745
• Main Authors: Khan, Mohammad Fareed, Mathur, Alpana, Pandey, Vivek Kumar, Kakkar, Poonam
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - metabolism; Animals; Apoptosis - drug effects; Cell Cycle Proteins - metabolism; Cell Line; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Endoplasmic Reticulum Stress - drug effects; ER Stress; Flavanones - pharmacology; Flavanones - therapeutic use; Forkhead Box Protein O1 - metabolism; FoxO1; Hyperglycemia - complications; Hyperglycemia - metabolism; Hyperglycemic nephrotoxicity; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Naringenin; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Rats; Rats, Wistar; Signal Transduction - drug effects; TRB3; Unfolded protein response
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2022.174745

Endoplasmic reticulum (ER) dysfunction contributes greatly to the pathophysiology of hyperglycemic nephrotoxicity. This study unravels the critical role of Tribbles 3 (TRB3)-Forkhead box O1 (FoxO1) signaling pathway during hyperglycemic renal toxicity. It also uncovers the novel role of Naringenin, a flavanone, in regulating ER stress in proximal tubular cells, NRK 52E, and kidneys of streptozotocin/nicotinamide induced experimental diabetic Wistar rats. Results demonstrate that expression of ER stress marker proteins including phosphorylated protein kinase ER like kinase (p-PERK), phosphorylated eukaryotic Initiation Factor 2α (p-eIF2α), X Box Binding Protein 1 spliced (XBP1s), Activating Transcription Factor 4 (ATF4) and C/EBP Homologous Protein (CHOP) were upregulated in diabetic kidneys indicating the activation of ER stress response due to nephrotoxicity. Treatment with Naringenin reduced the expression of TRB3, an ER stress-inducible pseudokinase, both in vitro and in vivo. Gene silencing of TRB3 enhanced Akt and FoxO1 phosphorylation and alleviated FoxO1 mediated apoptosis during hyperglycemic nephrotoxicity. Notably, TRB3 gene silencing effects were comparable to the response with Naringenin treatment. Prevention of nuclear colocalization of ATF4 and CHOP in Naringenin treated cells was evident. Naringenin also reduced insulin resistance, apoptosis and glycogen accumulation along with enhancement of glucose tolerance in diabetic rats. Prevention of ultrastructural aberrations in the ER of hyperglycemic renal cells by Naringenin confirmed its anti-ER stress effects. These findings affirm that activation of TRB3-FoxO1 signaling is critical in the pathogenesis of hyperglycemia-induced renal toxicity and protective effect of Naringenin via modulation of ER stress may be exploited as a novel approach for its management. [Display omitted] •UPR sensor proteins were upregulated indicating ER stress during hyperglycemia.•Aberrant ER stress response induces TRB3 expression in vitro and in vivo.•Gene silencing of TRB3 prevented renal cell death during hyperglycemic nephrotoxicity.•Anti-ER stress effects of Naringenin were comparable to effects of TRB3 gene silencing.•Naringenin attenuated ER stress and TRB3-FoXO1 dependent responses.