Activation of the NAD⁺–Sirtuin Axis Protects Against Chronic Doxorubicin-Induced Subclinical Renal Tubular Injury Through Restoration of Mitochondrial Homeostasis and Suppression of Inflammation
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Background and purpose
Anthracyclines, such as doxorubicin (DOX), are associated with late-onset kidney dysfunction; however, the mechanisms underlying chronic tubular injury remain poorly understood. We investigated whether chronic low-dose DOX exposure induces persistent mitochondrial dysfunction in renal tubules and evaluated the therapeutic potential of activating the NAD⁺–Sirtuin axis.
Experimental Approach
C57BL/6 mice were repeatedly administered low-dose DOX with or without resveratrol (RSV) or nicotinamide mononucleotide (NMN), a sirtuin activator. Renal injury was assessed using neutrophil gelatinase-associated lipocalin (NGAL) staining. Integrated proteomic and RNA sequencing analyses were performed to identify molecular alterations. Mitochondrial morphology and function were evaluated using structured illumination microscopy (SIM) of Masson’s trichrome-stained paraffin sections and ex vivo Seahorse analysis of freshly isolated renal tubules.
Key Results
Chronic DOX administration induced tubular injury, despite preserving serum creatinine levels. Multi-omics analyses consistently demonstrated the suppression of mitochondrial pathways, including oxidative phosphorylation, fatty acid oxidation, and mitochondrial gene expression. SIM revealed mitochondrial fragmentation in tubular epithelial cells, whereas the Seahorse assay showed impaired mitochondrial respiratory capacity in isolated renal tubules. DOX also increased tubular acetylated superoxide dismutase 2 (SOD2) levels and activated inflammatory pathways. Importantly, both RSV and NMN attenuated tubular injury, restored mitochondrial metabolic pathways, reduced SOD2 acetylation, improved mitochondrial morphology, and suppressed inflammatory responses.
Conclusions and Implications
Chronic low-dose DOX exposure induces subclinical renal tubular injury characterized by mitochondrial dysfunction and inflammation. The pharmacological activation of sirtuins confers reno-protective effects by preserving mitochondrial homeostasis. These findings identify mitochondrial dysfunction as a central therapeutic target in DOX-induced nephrotoxicity and support sirtuin modulation as a potential strategy for preventing chemotherapy-related chronic kidney injury.
Bullet point summary
What is already known
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Doxorubicin causes cardiotoxicity through mitochondrial dysfunction and oxidative stress.
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Doxorubicin-induced tubular injury and the associated late-onset kidney dysfunction are clinically proven.
What does this study add
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Chronic low-dose doxorubicin induces tubular mitochondrial dysfunction, as identified by integrated multi-omics analyses.
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Resveratrol and NMN preserve mitochondrial integrity and suppress inflammatory responses in renal tubules.
Clinical significance
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Mitochondrial dysfunction may represent an early therapeutic target in doxorubicin-associated nephrotoxicity.
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Activation of the NAD⁺–Sirtuin axis could prevent chronic kidney injury in cancer survivors.
