Metabolomics fingerprinting identifies redox-dependent inhibition of TXNIP alleviates renal fibrosis via modulation of TGF-β1/COL-1/ GRP78 signaling axis in a diabetic nephropathy rat model.

Authors

Karan Singh Yadav, Gurvinder Singh, Sharmeen Ishteyaque, Shobhit Verma, Smriti Verma, Manisha Yadav, Anurag Kumar Srivastava, Dinesh Kumar, Madhav Nilakanth Mugale

Published in

Free radical biology & medicine. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

Diabetic nephropathy (DN) is a chronic metabolic disorder characterized by hyperglycaemia-induced disruption of renal homeostasis. Emerging evidence suggests that the TRX/TXNIP axis mediates oxidative stress and inflammation in DN. However, its specific role in regulating ER-mitochondrial dysfunction and renal fibrosis remains unclear. Streptozotocin (STZ)-induced diabetic rats exhibited a progressive decline in body weight and increased feed consumption from the 6^th week onward. These rats showed reduced renal antioxidant levels and elevated malondialdehyde (MDA) concentrations. Histopathological analysis revealed renal structural alterations, impaired kidney function, and increased accumulation of glycogen and type I collagen over time. Additionally, DN progression was associated with a gradual upregulation of TXNIP, α-SMA, and p-NF-κB, as demonstrated by immunohistochemistry. Immunoblot analysis revealed increased expression of TXNIP, COL-1, and TGF-β1, accompanied by decreased levels of TXN-2 and beclin-1. Silencing of TXNIP alleviated ER-mitochondrial dysfunction (GRP78 and DRP-1), reduced apoptosis (decreased cleaved caspase 3 and increased Bcl-2 levels), and suppressed fibrogenic markers (TGF-β1 and COL-1) in NRK-52E cells exposed to high glucose (HG). Furthermore, we performed integrated high-field 800 MHz Nuclear Magnetic Resonance (NMR) based metabolomics analysis of renal tissues to identify metabolic signatures associated with DN progression. The findings revealed time-dependent accumulation of branched-chain amino acids and decreased myo-inositol levels across all intervention groups during the progression of DN. Collectively, these findings suggest that the TRX/TXNIP axis contributes to renal fibrosis through ER-mitochondrial cross-talk and metabolic alterations during the development of DN.

PMID:
42580538
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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