Kidney ischemia/reperfusion injury causes cholangiocytes primary cilia disruption and abnormal bile secretion.

BACKGROUND: Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle). METHODS: Cystathione γ-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC). RESULTS: KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione ß-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion. CONCLUSIONS: These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.

Short-term control of diet affects cisplatin-induced acute kidney injury through modulation of mitochondrial dynamics and mitochondrial GSH.

Obesity affects acute kidney injury (AKI) induced by various clinical settings, including transplantation and cisplatin-cancer therapy. However, the effect of short-term food intake change remains to be defined. Here, we investigated the effects of short-term high-fat diet intake and food restriction on cisplatin-induced AKI. Mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) for 11 days or were not fed for 40 hh (fasting), before cisplatin administration. Cisplatin-induced functional and structural damages to kidneys in both HFD- and LFD-fed mice, with greater damages in HFD-fed mice than LFD-fed mice. HFD decreased mitochondrial total glutathione (tGSH) level, along with increases in the plasma and kidney cholesterol levels. Cisplatin caused the increase of kidney cholesterol levels and oxidative stress, along with the decrease of mitochondrial tGSH levels. In addition, cisplatin-induced mitochondrial damage and apoptosis of tubular cells in both HFD- and LFD-fed mice. An increase of Fis1 (mitochondria fission 1 protein), whereas a decrease of Opa1 (mitochondria fusion 1 protein) occurred by cisplatin. These cisplatin effects were greater in HFD-fed mice than in LFD-fed mice. Administration of mitochondria-specific antioxidant treatment during HFD feeding inhibited these cisplatin-induced changes. Fasting for 40 h also significantly reduced the cisplatin-induced changes mentioned above. These data demonstrate that short-term HFD intake worsens cisplatin-induced oxidative stress by the reduction of mitochondrial tGSH, resulting in increased cisplatin-induced nephrotoxicity. These data newly indicate that the control of calorie intake, even for a short period, affects kidney susceptibility to injury. Although most studies described the effects of a long-term high-fat diet on the kidneys, in this study, we found that even if a high-fat diet was consumed for a short-term, physiological changes and mitochondria tGSH decrease in the kidneys, and consequently increased cisplatin-nephrotoxic susceptibility. These data suggest the association of calorie intake with kidney susceptibility to cisplatin.

Cisplatin induces lung cell cilia disruption and lung damage via oxidative stress.

BACKGROUND: Cisplatin (cis-diamminedichloroplatinum II) is widely used for the treatment of cancer, but its cellular toxicity, especially in the form of oxidative stress, limits its use in multiple organs including the lungs. As a cellular organelle, cilia play an important role in cellular function and can be damaged by oxidative stress. However, the effect of cisplatin-induced lung toxicity on cilia has not yet been defined. Herein, we investigated the association of cilia and oxidative stress with cisplatin-induced lung damage. METHODS: Mice were administered with cisplatin. Some mice were treated with 2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (Mito-TEMPO, a mitochondria-specific antioxidant) before the administration of cisplatin. Disruption of cilia was evaluated by the detection of ciliary proteins and fragments in the bronchoalveolar lavage fluid (BALF). RESULTS: Cisplatin caused the thickening of interalveolar septa, infiltration of immune cells into the interalveolar septa, and increased protein concentration and total cell number in the BALF. Cisplatin also increased ciliary fragments and proteins in the BALF. In the lungs, cisplatin increased the production of hydrogen peroxide, lipid peroxidation, and apoptosis, while decreasing manganese superoxide dismutase, isocitrate dehydrogenase 2, and catalase expression. Treatment with Mito-TEMPO prevented cisplatin-induced lung damage, ciliary fragmentation, oxidative stress, and apoptosis. CONCLUSION: By increasing oxidative stress in the lung, cisplatin induces lung cell damage, disruption of cilia, and release of disrupted cilia into the BALF. This suggests that cisplatin-induced lung damage can damage the cilia, manifesting as increased ciliary proteins in the BALF.

Oxidative stress following acute kidney injury causes disruption of lung cell cilia and their release into the bronchoaveolar lavage fluid and lung injury, which are exacerbated by Idh2 deletion.

Acute kidney injury (AKI) induces distant organ injury, which is a serious concern in patients with AKI. Recent studies have demonstrated that distant organ injury is associated with oxidative stress of organ and damage of cilium, an axoneme-based cellular organelle. However, the role of oxidative stress and cilia damage in AKI-induced lung injury remains to be defined. Here, we investigated whether AKI-induced lung injury is associated with mitochondrial oxidative stress and cilia disruption in lung cells. AKI was induced in isocitrate dehydrogenase 2 (Idh2, a mitochondrial antioxidant enzyme)-deleted (Idh2-/-) and wild-type (Idh2+/+) mice by kidney ischemia-reperfusion (IR). A group of mice were treated with Mito-TEMPO, a mitochondria-specific antioxidant. Kidney IR caused lung injuries, including alveolar septal thickening, alveolar damage, and neutrophil accumulation in the lung, and increased protein concentration and total cell number in bronchoalveolar lavage fluid (BALF). In addition, kidney IR caused fragmentation of lung epithelial cell cilia and the release of fragments into BALF. Kidney IR also increased the production of superoxide, lipid peroxidation, and mitochondrial and nuclei DNA oxidation in lungs and decreased IDH2 expression. Lung oxidative stress and injury relied on the degree of kidney injury. Idh2 deletion exacerbated kidney IR-induced lung injuries. Treatment with Mito-TEMPO attenuated kidney IR-induced lung injuries, with greater attenuation in Idh2-/- than Idh2+/+ mice. Our data demonstrate that AKI induces the disruption of cilia and damages cells via oxidative stress in lung epithelial cells, which leads to the release of disrupted ciliary fragments into BALF.