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

JCI Insight. 2018 Sep 20;3(18):e99592. doi: 10.1172/jci.insight.99592.

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.

Keywords: Autophagy; COPD; Chronic kidney disease; Nephrology; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Animals
  • Autophagy
  • Beclin-1 / genetics
  • Beclin-1 / metabolism*
  • Cell Line
  • Cell Survival
  • Disease Models, Animal
  • Epithelial Cells
  • Female
  • Fibrosis
  • Gene Expression Profiling
  • Humans
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria
  • Oxidative Stress
  • Pulmonary Disease, Chronic Obstructive / complications*
  • Smoke / adverse effects*
  • Tobacco / adverse effects*

Substances

  • Beclin-1
  • Becn1 protein, mouse
  • Smoke