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<p>Diabetic kidney nephropathy (DKN) is the leading cause of end-stage renal disease, driven by hyperglycemia-induced metabolic and inflammatory processes. Myo-inositol oxygenase (MIOX), a kidney-specific enzyme involved in myo-inositol catabolism, contributes to oxidative stress and inflammation in DKN. Another key regulator, the nuclear factor of activated T-cells 5 (NFAT5), plays a critical role in cellular responses to osmotic stress and kidney injury. While the individual roles of MIOX and NFAT5 in DKN are well established, their interplay and transcriptional regulation in disease progression remain unclear. Therefore, we hypothesized that the MIOX-NFAT5 axis contributes to DKN pathogenesis by driving transcriptional reprogramming and activating proinflammatory, proapoptotic, and profibrotic pathways. To investigate this, diabetes was induced in experimental rats using a single intraperitoneal (i.p.) dose of streptozotocin, and disease progression was monitored for 180 days. DKN-induced rats exhibited increased blood glucose and proteinuria levels. Histopathological analysis revealed glomerular hypertrophy, mesangial expansion, glomerular basement membrane thickening, podocyte injury, and tubulointerstitial fibrosis. Expression analysis demonstrated two-fold increase (<i>p</i> &lt; <i>0.05</i>) in co-expression of MIOX and NFAT5, along with key transcription factors, including NFκB, GATA4, FoxO1, TGFβ, c-Jun, and Src1. Additionally, apoptotic markers P53, Bax, and caspase-3 were upregulated, while Bcl-2 expression was reduced. These findings suggest that transcriptional regulation of the MIOX-NFAT5 axis plays a crucial role in promoting inflammation, apoptosis, and fibrosis in DKN. In conclusion, our study highlights the significance of the MIOX-NFAT5 axis in DKN pathogenesis and suggests that targeting its transcriptional regulators may offer potential therapeutic strategies for mitigating disease progression.</p>

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MIOX-NFAT5 Axis in Diabetic Kidney Nephropathy: Transcriptional Regulation and Pathogenic Mechanisms

  • 期刊论文

  • 发表日期：

    2026年1月9日

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  • Chalikkaran Thilakan Rejani,
  • Vijayapoopathi Singaravel,
  • Venugopal Bhuvarahamurthy

摘要

Diabetic kidney nephropathy (DKN) is the leading cause of end-stage renal disease, driven by hyperglycemia-induced metabolic and inflammatory processes. Myo-inositol oxygenase (MIOX), a kidney-specific enzyme involved in myo-inositol catabolism, contributes to oxidative stress and inflammation in DKN. Another key regulator, the nuclear factor of activated T-cells 5 (NFAT5), plays a critical role in cellular responses to osmotic stress and kidney injury. While the individual roles of MIOX and NFAT5 in DKN are well established, their interplay and transcriptional regulation in disease progression remain unclear. Therefore, we hypothesized that the MIOX-NFAT5 axis contributes to DKN pathogenesis by driving transcriptional reprogramming and activating proinflammatory, proapoptotic, and profibrotic pathways. To investigate this, diabetes was induced in experimental rats using a single intraperitoneal (i.p.) dose of streptozotocin, and disease progression was monitored for 180 days. DKN-induced rats exhibited increased blood glucose and proteinuria levels. Histopathological analysis revealed glomerular hypertrophy, mesangial expansion, glomerular basement membrane thickening, podocyte injury, and tubulointerstitial fibrosis. Expression analysis demonstrated two-fold increase (p < 0.05) in co-expression of MIOX and NFAT5, along with key transcription factors, including NFκB, GATA4, FoxO1, TGFβ, c-Jun, and Src1. Additionally, apoptotic markers P53, Bax, and caspase-3 were upregulated, while Bcl-2 expression was reduced. These findings suggest that transcriptional regulation of the MIOX-NFAT5 axis plays a crucial role in promoting inflammation, apoptosis, and fibrosis in DKN. In conclusion, our study highlights the significance of the MIOX-NFAT5 axis in DKN pathogenesis and suggests that targeting its transcriptional regulators may offer potential therapeutic strategies for mitigating disease progression.