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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 1

CS induces kidney injury in a murine model of COPD.

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CS induces kidney injury in a murine model of COPD.
Kidney sections from...
Kidney sections from mice exposed to room air (RA) or cigarette smoke (CS) for 6 months were stained with (A) Masson’s trichrome or (B) Sirius red. Scale bars: 50 μm and 25 μm (magnified images). (C) Western blot for fibronectin expression in kidneys after RA or CS exposure (n = 7 for each group), representative of 3 independent experiments. Graph represents quantification of Western blot data normalized to β-actin and RA control. (D) Periodic acid–Schiff (PAS) staining of kidney tissue from mice exposed to CS for 6 months, showing increased glomerular basement matrix content (arrowhead) relative to RA control. Scale bars: 25 μm. (E) Transmission electron microscopy (TEM) of kidney sections after 6 months of CS exposure, displaying podocyte foot process effacement (black arrow) and glomerular basement membrane thickening (black arrowhead), interstitial collagen deposition (red arrowhead), and cytoplasmic lipid droplets in tubular cells (red arrow) relative to RA control. Scale bars: 2 μm and 500 nm (collagen deposition in CS group). (F) Urine neutrophil gelatinase–associated lipocalin (NGAL) levels quantified by ELISA (mg/dl), normalized to urine creatinine after 6 months of CS exposure (n = 6 per group). All data are mean ± SEM. *P < 0.05, ***P < 0.001 by 2-tailed Student’s t test.

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