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bioRxiv · 10.64898/2025.12.27.696702

Temporal Dynamics of Kidney Mitochondrial Dysfunction in Type 2 Diabetes: Analysis of the Goto-Kakizaki Model.

Castino, B.·Jorge, L.·Santos, A. A.·Bachi, A. L.·Borges, F. T.
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Abstract

Type 2 diabetes mellitus (T2DM) is a major cause of diabetic kidney disease (DKD), a complication driven by chronic hyperglycemia, oxidative stress, and inflammation. Mitochondrial dysfunction has been recognized as a central feature of DKD, but the temporal relationship between mitochondrial alterations, mitophagy, and inflammatory responses remains unclear. Using the non-obese Goto-Kakizaki (GK) rat, a spontaneous model of T2DM, we examined renal mitochondrial changes at 21, 60, and 120 days. Histology revealed a trend toward increased glycation product deposition, more evident at 60 days. Cytochrome C and OPA-1 expression indicated early mitochondrial adaptation through enhanced respiratory activity and hyperfusion, while reduced PGC1- and PINK suggested impaired biogenesis and mitophagy. By 120 days, PGC1- and PINK increased, likely reflecting delayed, insufficient compensation, coinciding with mitochondrial depolarization. Cytokine analysis revealed a biphasic inflammatory profile: IL-18 and CXCL1 were sharply elevated at 21 days, IL-1{beta} remained stable, and IL-10 was elevated at 21 and 60 days, indicating early pro-inflammatory activation followed by anti-inflammatory modulation. These findings suggest that renal mitochondrial dysfunction in GK rats evolves from an adaptive state to late-stage failure, with inflammation occurring as transient peaks rather than a persistent process. The period between 21 and 60 days emerges as a critical therapeutic window in which strategies to preserve mitochondrial quality control and modulate inflammasome-related responses may be most effective.

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Castino, B., Jorge, L., Santos, A. A., Bachi, A. L., Borges, F. T.. 2025-12-27. Temporal Dynamics of Kidney Mitochondrial Dysfunction in Type 2 Diabetes: Analysis of the Goto-Kakizaki Model.. https://doi.org/10.64898/2025.12.27.696702

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