Diabetes aggravates renal ischemia-reperfusion injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy

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.

Mitochondrial Regulation of Diabetic Kidney Disease

“…The kidney has been shown to have a high rate of mitophagy relative to other organs, as well as cell type dependent regulation where podocytes have greater levels of mitophagy relative to tubules (211,212). Increased mitophagy has been shown to be protective in models of CKD, DKD, and AKI (213)(214)(215)(216)(217)(218)(219)(220). The PINK1/PRKN pathway is activated by oxidative stress established in DKD whereas treatment with the mitochondrial antioxidant, MitoQ, has been suggested to protect from DKD by increasing mitophagy levels (218).…”

Pioglitazone in diabetic kidney disease: forgotten but not gone

“…It promotes the accumulation of extracellular matrix that destroys normal renal architecture; eventually it promotes fibrosis [ 84 ]. Moreover, ample evidence suggests that diabetes can enhance the sensitivity to renal ischemia/reperfusion injury (IRI) through: (i) repression of mitochondrial function and mitophagy; (ii) stimulation of inflammation, oxidative stress, and apoptosis; and (iii) evolution of diffuse tubular necrosis [ 85 , 86 ].…”

Penicilliumin B Protects against Cisplatin-Induced Renal Tubular Cell Apoptosis through Activation of AMPK-Induced Autophagy and Mitochondrial Biogenesis

“…4d-f. We next assessed the expression of PTEN-induced putative kinase protein 1 (PINK1), which is an initiator of mitophagy by anchoring to the outer membrane of depolarized mitochondria [32]. As shown in Fig.…”