Leukocytes induce epithelial to mesenchymal transition after unilateral ureteral obstruction in neonatal mice.
Urinary tract obstruction during renal development leads to tubular apoptosis, tubular atrophy, and interstitial fibrosis. Epithelial to mesenchymal transition (EMT) has been proposed as a key mechanism of myofibroblast accumulation in renal fibrosis. We studied the interplay of leukocyte infiltration, tubular apoptosis, and EMT in renal fibrosis induced by unilateral ureteral obstruction (UUO) in neonatal mice. We show that leukocytes mediate tubular apoptosis and EMT in the developing kidney with obstructive nephropathy. Blocking leukocyte recruitment by using the chemokine receptor-1 antagonist BX471 protected against tubular apoptosis and interstitial fibrosis, as evidenced by reduced monocyte influx, a decrease in EMT, and attenuated collagen deposition. EMT was rapidly induced within 24 hours after UUO along with up-regulation of the transcription factors Snail1 and Snail2/Slug, preceding the induction of alpha-smooth muscle actin and vimentin. In the presence of BX471, the expression of chemokines, as well as of Snail1 and Snail2/Slug, in the obstructed kidney was completely attenuated. This was associated with reduced macrophage and T-cell infiltration, tubular apoptosis, and interstitial fibrosis in the developing kidney. Our findings provide evidence that leukocytes induce EMT and renal fibrosis after UUO and suggest that chemokine receptor-1 antagonism may prove beneficial in obstructive nephropathy.
Department of Pediatrics, Ruprecht-Karls-University, Heidelberg, Germany. baerbel.lange-sperandio@med.uni-muenchen.de
Bärbel
B
Lange-Sperandio
Agnes
A
Trautmann
Oliver
O
Eickelberg
Aparna
A
Jayachandran
Stephan
S
Oberle
Florian
F
Schmidutz
Barbara
B
Rodenbeck
Meike
M
Hömme
Richard
R
Horuk
Franz
F
Schaefer
D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D004848:Epithelium / Q000502:physiology*; D005355:Fibrosis / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010671:Phenylurea Compounds / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014513:Ureter / Q000473:pathology*
D000199:Actins; D018925:Chemokines; D010671:Phenylurea Compounds; D010880:Piperidines; D019707:Receptors, Chemokine; C000604429:Snai1 protein, mouse; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C411885:BX 471