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

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 7

Becn1+/– mice have decreased mitophagy at baseline that does not increase after cigarette smoke exposure.

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Becn1+/– mice have decreased mitophagy at baseline that does not increa...
(A) Mitochondria of renal tubular epithelial cells of WT mice exposed to cigarette smoke (CS), showing invaginations (arrow) and loss of mitochondrial matrix (arrowhead) relative to RA control. Scale bars: 500 nm (top) and 200 nm (bottom). (B) Quantification of LC3B detected in mitochondrial fractions from WT mice, normalized to TOM20 and room air (RA) control (n = 9 for RA, n =10 for CS). (C) Representative Western blot of NDP52 in mitochondrial fractions from WT mice exposed to 6 months of CS compared with RA. Graph represents quantification of Western data normalized to TOM20 and RA control (n = 9 for RA, n = 10 for CS). (D) Quantification of Western blots of LC3B, NDP52, Parkin and (E) Mitochondrial transcription factor A (TFAM) expression detected in mitochondrial fractions after 6 months of CS or RA exposure in Becn1+/– mice relative to Becn1+/+ mice. Data were normalized to TOM20 and control (n = 10/group for Becn1+/+ mice, and n = 4/group for Becn1+/– mice). All data are mean ± SEM. *P < 0.05, **P < 0.01, analyzed by Student’s t test (B and C) and 1-way ANOVA with Bonferroni’s post hoc test (D and E). (F) Diagram representing CS-induced kidney injury. After systemic exposure to CS, autophagy is upregulated in kidneys in association with kidney injury. Becn1+/– mice have reduced autophagy and display reduced kidney injury after CS exposure. The increased autophagic activity and autophagosome turnover in response to CS exposure reduces Beclin-1 steady-state levels, as a potential compensatory mechanism.