Abstract
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 (Atg7flox/flox;KAP-Cre+). Analysis of renal tissue from two months old Atg7flox/flox;KAP-Cre+ 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 Atg7flox/flox;KAP-Cre+ 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 Atg7flox/flox;KAP-Cre+ 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.
Highlights
Renal proximal tubular epithelial cells reabsorb proteins from the glomerular filtrate that undergoes proteolysis by the lysosomal system [1,2]
Urinalysis, and blood biochemistry test results showed no significant difference between Atg7flox/flox and Atg7flox/flox;kidney androgen-regulated protein (KAP)-Cre+ mice in their renal function consistent with previous report (Supplementary Figure S1) [22]
The results show that Atg7 was significantly decreased in the kidneys of Atg7flox/flox;KAP-Cre+ mice compared with the kidneys of control mice (Figure 1A)
Summary
Renal proximal tubular epithelial cells reabsorb proteins from the glomerular filtrate that undergoes proteolysis by the lysosomal system [1,2]. We reported that renal ischemia/reperfusion injury results in an increase in kidney injury molecule (Kim-1), a marker for early kidney injury, in cathepsin D-deficient renal tubular epithelial cells [3]. Autophagy protects the cellular function of renal proximal tubular cells against injury induced by renal ischemia-reperfusion, nephrotoxic drugs, and ureteral obstruction injury. There is no apparent defect in kidney function of renal tubular cell-specific autophagy-deficient mouse under normal fed conditions [17,18,19]. There are few reports of intracellular abnormalities in autophagy-deficient renal proximal tubular cells under normal fed conditions. Considering the increased sensitivity of autophagy-deficient renal tubular cells against acute kidney injury, it is possible that autophagy plays an indispensable role in maintaining normal functioning. To clarify the intracellular function of autophagy in the renal proximal tubular cells, we targeted the Atg gene, and generated a renal proximal tubular cell-specific knockout mouse (Atg7flox/flox;KAP-Cre+)
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