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Beclin-1 regulates cigarette smoke–induced kidney injury in a murine model of chronic obstructive pulmonary disease
Maria A. Pabón, … , Suzanne M. Cloonan, Mary E. Choi
Maria A. Pabón, … , Suzanne M. Cloonan, Mary E. Choi
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e99592. https://doi.org/10.1172/jci.insight.99592.
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Research Article Nephrology Pulmonology

Beclin-1 regulates cigarette smoke–induced kidney injury in a murine model of chronic obstructive pulmonary disease

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Abstract

Chronic obstructive pulmonary disease (COPD), associated with cigarette smoke–induced (CS-induced) emphysema, contributes significantly to the global health care burden of disease. Although chronic kidney disease (CKD) may occur in patients with COPD, the relationship between COPD and CKD remains unclear. Using a murine model of experimental COPD, we show that chronic CS exposure resulted in marked kidney injury and fibrosis, as evidenced by histological and ultrastructural changes, altered macrophage subpopulations, and expression of tissue injury, fibrosis, and oxidative stress markers. CS induced mitochondrial dysfunction, and increased autophagic flux in kidney tissues and in kidney tubular epithelial (HK-2) cells, as determined by LC3B turnover assays. Mice heterozygous for Beclin-1 (Becn1+/–) were protected from the development of kidney tissue injury and renal fibrosis in response to CS exposure, and displayed impaired basal and inducible mitochondrial turnover by mitophagy. Interestingly, CS caused a reduction of Beclin-1 expression in mouse kidneys and kidney tubular epithelial cells, attributed to increased autophagy-dependent turnover of Beclin-1. These results suggest that Beclin-1 is required for CS-induced kidney injury and that reduced levels of Beclin-1 may confer renoprotection. These results identify the kidney as a target for CS-induced injury in COPD and the Beclin-1–dependent autophagy pathway as a potential therapeutic target in CKD.

Authors

Maria A. Pabón, Edwin Patino, Divya Bhatia, Joselyn Rojas-Quintero, Kevin C. Ma, Eli J. Finkelsztein, Juan C. Osorio, Faryal Malick, Francesca Polverino, Caroline A. Owen, Stefan W. Ryter, Augustine M.K. Choi, Suzanne M. Cloonan, Mary E. Choi

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Figure 2

CS induces oxidative stress and mitochondrial injury in a murine model of COPD.

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CS induces oxidative stress and mitochondrial injury in a murine model o...
(A) Nitrotyrosine and (B) 8-Oxo-2′-deoxyguanosine (8-oxo-DG) staining detected by immunohistochemical staining of kidney tissue of mice exposed to room air (RA) or cigarette smoke (CS) for 6 months. Scale bars: 50 μm and 25 μm (magnified images). (C) Quantification of Nrf2 expression measured by Western blot in kidney tissue from mice exposed to RA or CS for 6 months (n = 4 in each group) normalized to β-actin and control. Data are mean ± SEM. *P < 0.05, analyzed by Student’s t test. (D) Transmission electron microscopy (TEM) of kidney sections harvested after 6 months of CS exposure, depicting mitochondrial swelling and loss of cristae definition, compared with RA control. Scale bars: 1 μm and 0.5 μm (magnified images). (E) Quantification of mitochondrial membrane potential of HK-2 cells treated in vitro with increasing concentrations of CS extract (CSE), measured by tetramethylrhodamine ethyl ester (TMRE) detected by FACS. Data are mean ± SEM. *P < 0.05 by 1-way ANOVA with Bonferroni’s post hoc test. (F) Representative Western blot of mitochondrial transcription factor A (TFAM) expression in kidneys after 6 months of CS exposure (3 independent determinations), with quantification (n = 8 per group). Data were normalized to TOM20 and RA control. All data are mean ± SEM. *P < 0.05 by 2-tailed Student’s t test.

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