Angiotensin II contributes to renal fibrosis independently of Notch pathway activation.
Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.
Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma, Madrid, Spain.
Carolina
C
Lavoz
Raquel
R
Rodrigues-Diez
Alberto
A
Benito-Martin
Sandra
S
Rayego-Mateos
Raúl R
RR
Rodrigues-Diez
Matilde
M
Alique
Alberto
A
Ortiz
Sergio
S
Mezzano
Jesús
J
Egido
Marta
M
Ruiz-Ortega
D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006869:Hydronephrosis / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000494:pharmacology
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D044140:Receptor, Angiotensin, Type 1; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II