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Endoplasmic reticulum stress-dependent activation of TRB3-FoxO1 signaling pathway exacerbates hyperglycemic nephrotoxicity: Protection accorded by Naringenin.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2022 Feb 15; Vol. 917, pp. 174745. Date of Electronic Publication: 2022 Jan 05. - Publication Year :
- 2022
-
Abstract
- 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.<br /> (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Male
Rats
Diabetes Mellitus, Experimental metabolism
Diabetes Mellitus, Experimental complications
Diabetes Mellitus, Experimental drug therapy
Forkhead Box Protein O1 metabolism
Apoptosis drug effects
Kidney drug effects
Kidney metabolism
Kidney pathology
Protein Serine-Threonine Kinases metabolism
Protein Serine-Threonine Kinases antagonists & inhibitors
Cell Line
Cell Cycle Proteins metabolism
Diabetic Nephropathies metabolism
Diabetic Nephropathies pathology
Diabetic Nephropathies drug therapy
Activating Transcription Factor 4 metabolism
Endoplasmic Reticulum Stress drug effects
Flavanones pharmacology
Flavanones therapeutic use
Signal Transduction drug effects
Hyperglycemia metabolism
Hyperglycemia complications
Rats, Wistar
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 917
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 34998792
- Full Text :
- https://doi.org/10.1016/j.ejphar.2022.174745