Impacts of Metabolic Reprogramming on the Onset of Diabetic Nephropathy in Mice With Varying Lias Gene Expression Levels

Metabolic and energy reprogramming, potentially regulated by protein lipoylation, plays a critical role in maintaining kidney function and cell survival in diabetic kidney disease (DKD). However, it remains unclear whether improper reprogramming contributes to the onset of DKD. To investigate this issue, we developed a group of metabolic mouse models with varying levels of protein lipoylation, which resulted from distinct gene expression levels of lipoic acid synthase (Lias), and corresponding metabolic activity. Lias synthesizes α-lipoic acid, which can regulate mitochondrial function. We crossed these Lias metabolic models with Ins2Akita^/+ mice, a commonly used type 1 diabetes model that also exhibits the type 2 diabetes phenotype. These models allowed us to investigate the role of reprogramming and its regulation by protein lipoylation in initiating DKD. LiasH^/HIns2Akita^/+ mice, which had high metabolic activity associated with increased protein lipoylation levels, exhibited milder pathologic changes than LiasL^/LIns2Akita^/+ or Lias^+/+Ins2Akita^/+ mice in the early stages of DKD. These changes included reduced microalbuminuria, less expansion of the glomerular mesangial matrix, and decreased mitochondrial damage in proximal tubular epithelial cells. However, the beneficial effect was reduced in Lias gene knockdown, specifically within podocytes of LiasH^/HIns2Akita^/+ mice, achieved using the Cre-loxP system. This finding confirms that the increased protein lipoylation in podocytes helps attenuate DKD. Our study demonstrates that elevated protein lipoylation mitigates the early stages of DKD by influencing metabolic and energy reprogramming. This finding may offer a potential new strategy for preventing and treating DKD.

• Metabolic and energy reprogramming significantly affects renal cell function in diabetic kidney disease (DKD).
• We developed unique metabolic mouse models with varying levels of lipoic acid synthase (Lias) gene expression and correspondingly varying levels of protein lipoylation and metabolic activity.
• Using these metabolic mouse models, our study demonstrates that increased protein lipoylation can alleviate DKD through metabolic and energetic regulation.
• Our unique metabolic mouse models can serve as a preclinical platform to evaluate new therapeutic strategies, ultimately guiding translational studies for patients with DKD.

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