NFAT inhibitor tributylhexadecylphosphoniumbromide, ameliorates high fructose induced insulin resistance and nephropathy.

Abstract

High fructose diet (HFrD)-induced insulin resistance (IR) has been reported to be associated with an increase in albuminuria, glomerular hypertrophy and inflammation in kidney. However, the molecular mechanisms associated with high fructose-induced IR and renal dysfunction are still unclear. In the present study, we have investigated the role of nuclear factor of activated T-cell (NFAT) and its inhibitor, Tributylhexadecylphosphoniumbromide (THPB) in high fructose-induced IR and renal injury. NFAT inhibition by THPB treatment significantly improved HFrD-induced insulin resistance. Treatment with THPB markedly reduced high fructose diet-induced protein expression of NFATc4, PTEN and also alleviated expression of inflammatory markers in kidneys of HFrD rats. Further, THPB treatment not only improved acute ANG II responses but also repressed the processes of renal fibrosis, ECM accumulation, foot process effacement and renal apoptosis in HFrD rats. Taken together, we for the first time provide evidence that HFrD -induced insulin resistance and renal injury is associated with dysregulated NFATc4/PTEN signalling and THPB prevents this dysregulation through inhibition of NFATc4. Thus, targeting NFATc4 can be a novel therapeutic approach for preventing HFrD induced- IR and renal injury.

• Authors: Maitri Sanghavi, Malek Vajir, Sandeep Kumar, Kulbhushan Tikoo
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 240 Pg. 268-77 (Oct 05 2015) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 26358169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• NFATC Transcription Factors
• Organophosphorus Compounds
• tributylhexadecylphosphonium bromide
• Fructose
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Blotting, Western
• Body Weight (drug effects)
• Diabetic Nephropathies (chemically induced, drug therapy)
• Disease Models, Animal
• Fructose
• Gene Expression Regulation (drug effects)
• Insulin Resistance
• NFATC Transcription Factors (antagonists & inhibitors, genetics)
• Organophosphorus Compounds (pharmacology)
• PTEN Phosphohydrolase (genetics)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)