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Updated: Apr 18, 2026
Technical Refinement of a Bilateral Renal Ischemia-Reperfusion Mouse Model for Acute Kidney Injury Research
Published on: November 3, 2023
Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury
Abstract:
Acute kidney injury (AKI) is a public health concern with an annual mortality rate that exceeds those of breast and prostate cancer, heart failure, and diabetes combined. Oxidative stress and mitochondrial damage are drivers of AKI-associated pathology; however, the pathways that mediate these events are poorly defined. Here, using a murine cisplatin-induced AKI model, we determined that both oxidative stress and mitochondrial damage are associated with reduced levels of renal sirtuin 3 (SIRT3). Treatment with the AMPK agonist AICAR or the antioxidant agent acetyl-l-carnitine (ALCAR) restored SIRT3 expression and activity, improved renal function, and decreased tubular injury in WT animals, but had no effect in Sirt3-/- mice. Moreover, Sirt3-deficient mice given cisplatin experienced more severe AKI than WT animals and died, and neither AICAR nor ALCAR treatment prevented death in Sirt3-/- AKI mice. In cultured human tubular cells, cisplatin reduced SIRT3, resulting in mitochondrial fragmentation, while restoration of SIRT3 with AICAR and ALCAR improved cisplatin-induced mitochondrial dysfunction. Together, our results indicate that SIRT3 is protective against AKI and suggest that enhancing SIRT3 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury.
Insights
Sirtuin 3 (SIRT3) protects against acute kidney injury (AKI) by preventing oxidative stress and mitochondrial damage. Enhancing SIRT3 may improve outcomes for patients suffering from renal injury.
Area of Science:
- Nephrology
- Mitochondrial Biology
- Biochemistry
Background:
- Acute kidney injury (AKI) presents a significant public health challenge with high mortality rates.
- Oxidative stress and mitochondrial damage are key contributors to AKI pathology, but the underlying mechanisms remain unclear.
- Renal sirtuin 3 (SIRT3) levels are reduced in AKI, suggesting a potential role in disease progression.
Purpose of the Study:
- To investigate the role of SIRT3 in mediating kidney injury in a murine model of cisplatin-induced AKI.
- To determine if interventions targeting SIRT3 can ameliorate AKI and its associated pathologies.
- To explore the impact of SIRT3 on mitochondrial function and dynamics during renal injury.
Main Methods:
- Utilized a murine model of cisplatin-induced acute kidney injury (AKI).
- Administered AICAR (AMPK agonist) and acetyl-l-carnitine (ALCAR, antioxidant) to wild-type (WT) and Sirt3 knockout (Sirt3-/-) mice.
- Assessed renal function, tubular injury, oxidative stress, and mitochondrial integrity.
- Investigated SIRT3 expression and activity in cultured human tubular cells exposed to cisplatin.
Main Results:
- Cisplatin-induced AKI was associated with reduced renal SIRT3 levels, oxidative stress, and mitochondrial damage.
- AICAR and ALCAR treatments restored SIRT3, improved renal function, and reduced tubular injury in WT mice.
- Sirt3-/- mice exhibited exacerbated AKI, increased mortality, and did not benefit from AICAR or ALCAR treatment.
- In vitro, cisplatin reduced SIRT3 and caused mitochondrial fragmentation; AICAR and ALCAR restored SIRT3 and improved mitochondrial function.
Conclusions:
- SIRT3 plays a critical protective role in mitigating acute kidney injury.
- Enhancing SIRT3 activity and improving mitochondrial dynamics represent a promising therapeutic strategy for renal injury.
- Targeting SIRT3 may offer a novel approach to improve patient outcomes in AKI.
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01:29Acute Kidney Injury II: Pathophysiology
01:22Acute Kidney Injury I: Introduction
01:29Acute Kidney Injury III: Clinical Manifestations
01:20Acute Kidney Injury V: Interprofessional Care
01:45Mitochondrial Membranes