Reversal of renal lesions following interruption of nitric oxide synthesis inhibition in transgenic mice.
BACKGROUND
Renal fibrosis, a common complication of hypertension and diabetes is considered as a non-curable disease and is characterized by the abnormal accumulation of collagen I within the kidney. Chronic inhibition of nitric oxide (NO) synthesis is a model of hypertension associated with the development of nephroangiosclerosis. The present study investigated whether halt of NO inhibition leads to the regression of renal sclerotic lesions.


METHODS
The NO deficiency (N(G)-nitro-L-arginine methylester; L-NAME) model of hypertension was applied in transgenic mice harbouring the luciferase reporter gene under the control of the collagen I-alpha2 chain promoter.


RESULTS
Systolic pressure gradually increased following the administration of L-NAME, and reached 160 mmHg after 8-10 weeks. Activation of collagen I gene within the renal vasculature preceded the blood pressure increase and was accompanied by the appearance of sclerotic glomeruli and tubulointerstitial infiltration. After renal lesions had been established (20 weeks), animals were divided in three subgroups for an additional experimental period of 10 weeks: first group continued to receive L-NAME, in the second, L-NAME administration was stopped to allow endogenous NO synthesis and in the third the removal of L-NAME was combined with endothelin receptor antagonism. Removal of L-NAME decreased, without normalizing, systolic pressure and collagen I gene activity; renal morphology was substantially improved, and tubulointerstitial infiltration disappeared. Combination of L-NAME removal with endothelin antagonism normalized collagen I gene expression and further improved renal morphology without further decreasing blood pressure.


CONCLUSIONS
Manipulating the balance between NO/vasoconstrictors in favour of NO could provide a curative approach against renal inflammatory and fibrotic complications associated to hypertension.
Placier
Sandrine
S
INSERM U702, Hôpital Tenon, Pierre et Marie Curie University, Paris 75020, France.
Boffa
Jean-Jacques
JJ
Dussaule
Jean-Claude
JC
Chatziantoniou
Christos
C
D000818:Animals; D001794:Blood Pressure; D024042:Collagen Type I / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000502:physiology; D005786:Gene Expression Regulation; D006978:Hypertension, Renovascular / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D008156:Luciferases; D019331:NG-Nitroarginine Methyl Ester