Autophagy is a component of epithelial cell fate in obstructive uropathy.
Epithelial cell fate and nephron loss in obstructive uropathy are not fully understood. We produced transgenic mice in which epithelial cells in the nephrons and collecting ducts were labeled with enhanced yellow fluorescent protein, and tracked the fate of these cells following unilateral ureteral obstruction (UUO). UUO led to a decrease in the number of enhanced yellow fluorescent protein-expressing cells and down-regulation of epithelial markers, E-cadherin, and hepatocyte nuclear factor-1beta. Following UUO, enhanced yellow fluorescent protein-positive cells were confined within the tubular basement membrane, were not found in the renal interstitium, and did not express alpha-smooth muscle actin or S100A4, markers of myofibroblasts and fibroblasts. Moreover, when proximal tubules were labeled with dextran before UUO, dextran-retaining cells did not migrate into the interstitium or express alpha-smooth muscle actin. These results indicate that UUO leads to tubular epithelial loss but does not cause epithelial-to-mesenchymal transition that has been shown by others to be responsible for nephron loss and interstitial fibrosis. For the first time, we found evidence of enhanced autophagy in obstructed tubules, including accumulation of autophagosomes, increased expression of Beclin 1, and increased conversion of microtubular-associated protein 1 light chain 3-I to -II. Increased autophagy may represent a mechanism of tubular survival or may contribute to excessive cell death and tubular atrophy after obstructive injury.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA. linda.li@utsouthwestern.edu
Ling
L
Li
Diana
D
Zepeda-Orozco
Rachel
R
Black
Fangming
F
Lin
D000199:Actins / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy; D001426:Bacterial Proteins / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism; D000071186:Beclin-1; D015820:Cadherins / Q000378:metabolism; D019070:Cell Lineage; D004847:Epithelial Cells / Q000166:cytology*; D005347:Fibroblasts / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000096:biosynthesis; D014524:Urethral Obstruction / Q000473:pathology*
D000199:Actins; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D015820:Cadherins; D008164:Luminescent Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C054562:yellow fluorescent protein, Bacteria; D051539:Hepatocyte Nuclear Factor 1-beta