Autophagy Deficiency in Renal Proximal Tubular Cells Leads to an Increase in Cellular Injury and Apoptosis under Normal Fed Conditions

• Main Authors: Chigure Suzuki, Isei Tanida, Juan Alejandro Oliva Trejo, Soichiro Kakuta, Yasuo Uchiyama
• Format: Article
• Language: English
• Published: MDPI AG 2019-12-01
• Series: International Journal of Molecular Sciences
• Subjects: autophagy; <i>atg7</i>; renal proximal tubular cell; gene knockout mouse
• Online Access: https://www.mdpi.com/1422-0067/21/1/155

Renal proximal tubular epithelial cells are significantly damaged during acute kidney injury. Renal proximal tubular cell-specific autophagy-deficient mice show increased sensitivity against renal injury, while showing few pathological defects under normal fed conditions. Considering that autophagy protects the proximal tubular cells from acute renal injury, it is reasonable to assume that autophagy contributes to the maintenance of renal tubular cells under normal fed conditions. To clarify this possibility, we generated a knock out mouse model which lacks Atg7, a key autophagosome forming enzyme, in renal proximal tubular cells (<i>Atg7^flox/flox;KAP-Cre⁺</i>). Analysis of renal tissue from two months old <i>Atg7^flox/flox;KAP-Cre⁺</i> mouse revealed an accumulation of LC3, binding protein p62/sequestosome 1 (a selective substrate for autophagy), and more interestingly, Kim-1, a biomarker for early kidney injury, in the renal proximal tubular cells under normal fed conditions. TUNEL (TdT-mediated dUTP Nick End Labeling)-positive cells were also detected in the autophagy-deficient renal tubular cells. Analysis of renal tissue from <i>Atg7^flox/flox;KAP-Cre⁺</i> mice at different age points showed that tubular cells positive for p62 and Kim-1 continually increase in number in an age-dependent manner. Ultrastructural analysis of tubular cells from <i>Atg7^flox/flox;KAP-Cre⁺</i> revealed the presence of intracellular inclusions and abnormal structures. These results indicated that autophagy-deficiency in the renal proximal epithelial tubular cells leads to an increase in injured cells in the kidney even under normal fed conditions.