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Updated: Jan 21, 2026
An Effective Mouse Model of Unilateral Renal Ischemia-Reperfusion Injury
Published on: July 15, 2021
Diabetes aggravates renal ischemia-reperfusion injury by repressing mitochondrial function and PINK1/Parkin-mediated
Yuan-Yuan Yang1, Dao-Jing Gong1, Jian-Jian Zhang1
1Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Abstract:
Diabetes could aggravate ischemia-reperfusion (I/R) injury, but the underlying mechanism is unclear. In the present study, we aimed to investigate whether diabetes exacerbates renal I/R injury and its possible mechanism. In vitro, HK-2 cells under normal or high glucose conditions were subjected to hypoxia (12 h) followed by reoxygenation (3 h) (H/R). Cell viability, intracellular ATP content, mitochondrial membrane potential, reactive oxygen species production, and apoptosis were measured. In vivo, streptozotocin-induced diabetic and nondiabetic rats were subjected to I/R. Renal pathology, function, and apoptosis were evaluated by hematoxylin and eosin staining, transmission electron microscopy, and Western blot analysis. Compared with the normal glucose + H/R group, mitochondrial function (ATP, mitochondrial membrane potential, and reactive oxygen species) and mitophagy were reduced in the high glucose + H/R group, as was expression of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and Parkin. Also, cells in the high glucose + H/R group exhibited more apoptosis compared with the normal glucose + H/R group, as assessed by flow cytometry, TUNEL staining, and Western blot analysis. Compared with normal rats that underwent I/R, diabetic rats that underwent I/R exhibited more severe tubular damage and renal dysfunction as well as expression of the apoptotic protein caspase-3. Meanwhile, diabetes alleviated mitophagy-associated protein expression in rats subjected to I/R, including expression of PINK1 and Parkin. Transmission electron microscopy indicated that the mitophagosome could be hardly observed and that mitochondrial morphology and structure were obviously damaged in the diabetes + I/R group. In conclusion, our results, for the first time, indicate that diabetes could aggravate I/R injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy in vivo and in vitro.
Insights
Diabetes worsens kidney injury after blood flow is restored by impairing mitochondrial function and mitophagy. This study reveals the mechanism involves reduced PINK1/Parkin pathways, leading to increased cell death in diabetic conditions.
Area of Science:
- Nephrology
- Cell Biology
- Metabolic Diseases
Background:
- Diabetes mellitus is a known risk factor for various organ injuries.
- Ischemia-reperfusion (I/R) injury, particularly in the kidneys, can be exacerbated by diabetes, but the precise mechanisms remain incompletely understood.
Purpose of the Study:
- To investigate the impact of diabetes on renal ischemia-reperfusion (I/R) injury.
- To elucidate the underlying mechanisms, focusing on mitochondrial function and mitophagy.
Main Methods:
- In vitro: HK-2 cells exposed to high glucose and hypoxia/reoxygenation (H/R) to mimic diabetic conditions.
- In vivo: Streptozotocin-induced diabetic and control rats subjected to renal I/R.
- Evaluations included cell viability, mitochondrial function assays, apoptosis markers, Western blot for mitophagy proteins (PINK1, Parkin), and histological/ultrastructural analysis.
Main Results:
- High glucose conditions impaired mitochondrial function and reduced mitophagy, increasing apoptosis in vitro.
- Diabetic rats exhibited more severe renal pathology, dysfunction, and apoptosis compared to non-diabetic rats post-I/R.
- Diabetes significantly downregulated the expression of PINK1 and Parkin, crucial for mitophagy, and hindered mitophagosome formation.
Conclusions:
- Diabetes exacerbates renal I/R injury by suppressing mitochondrial function.
- The study identifies impaired PINK1/Parkin-mediated mitophagy as a key mechanism in diabetes-aggravated renal I/R injury.
- These findings offer novel insights into the pathophysiology of diabetic kidney injury and potential therapeutic targets.
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