[Vasoactive peptides and the development of renal sclerosis: contribution of transgenes].
Vasoactive peptides are implied in the development of renal sclerosis as evidenced by the efficiency of their antagonists in preventing glomerulosclerosis of experimental and human nephropathies. Genetically engineered models provide a new approach to investigate the mechanisms of the renal profibrotic actions of angiotensin II and endothelin. Overexpression of the human angiotensinogen and renin genes in rats induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed in mice. Transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[1]) and made hypertensive by induction of nitric oxide (NO) deficiency were used to study the renal profibrotic actions of vasoactive peptides. In this strain of mice, luciferase activity is an early index of renal fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were deficient in NO. The pharmacological blockade of angiotensin II and endothelin prevented the development of renal sclerosis without modifying blood pressure. Moreover, when the endothelin receptor antagonist was administered after the development of renal fibrosis, preformed glomerulosclerosis partially regressed. Acute administration of vasoactive peptides and TGF-beta in transgenic procol alpha 2[1] mice showed that the angiotensin II activation of collagen I gene requires participation and/or cooperation of endothelin and TGF-beta. Recent data suggest that the profibrotic actions of vasoactive peptides also need the activation of EGF receptor, ERK and rho kinase pathways in renal and vascular cells.
Dussaule
Jean-Claude
JC
Unité INSERM 489, Hôpital Tenon, 4 rue de la Chine, 75020, Paris.
Boffa
Jean-Jacques
JJ
Tharaux
Pierre-Louis
PL
Flamant
Martin
M
Fakhouri
Fadi
F
Chatziantoniou
Christos
C
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D024043:Collagen Type II / Q000235:genetics*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis; D017930:Genes, Reporter; D005923:Glomerulosclerosis, Focal Segmental / Q000517:prevention & control; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008156:Luciferases / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000172:deficiency / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012084:Renin-Angiotensin System / Q000502:physiology*; D012598:Sclerosis; D016212:Transforming Growth Factor beta / Q000502:physiology / Q000633:toxicity; D019076:Transgenes
D024043:Collagen Type II; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D009569:Nitric Oxide; D008156:Luciferases; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester