Age-dependent hypertension in Mpv17-deficient mice, a transgenic model of glomerulosclerosis and inner ear disease.
The mutant mouse strain Mpv17-/-, carries a retroviral germline integration that inactivates the Mpv17 gene. Mpv17-deficient mice develop progressive glomerulosclerosis and sensineural deafness at early age. Characteristic basement membrane alterations are found in both sites of pathology. Mpv17 is a peroxisomal protein involved in the metabolism of reactive oxygen species, yet its molecular function is unknown. Dysregulation of antioxidant enzymes and basal membrane components has been established in this model and successful therapeutic intervention with antioxidants prove the causal role of reactive oxygen species in the development of the disease phenotype. We here investigated if the Mpv17-/- mice might be hypertensive. Indeed, our study revealed that Mpv17-/- mice developed significant systemic hypertension and tachycardia between 4 weeks and 5 months of age, accompanied by polyuria and elevated natriuresis. Judging from serum and urine parameters, the hypertensive condition develops concomitantly with the renal disease. Biochemical and pharmacological studies that used the endothelin receptor antagonist bosentan and the angiotensin converting enzyme inhibitor cilazapril indicated no involvement of the endothelin and renin-angiotensin systems in this hypertension, suggesting a potential novel mechanism of blood pressure regulation in this new murine hypertension model. Thus, Mpv17-/- mice unravel an intriguing new association between a defect in reactive oxygen metabolism and the age-dependent development of hypertension.
Clozel
M
M
Actelion, Innovation Center, Allschwil, Switzerland.
Hess
P
P
Fischli
W
W
Löffler
B M
BM
Zwacka
R M
RM
Reuter
A
A
Weiher
H
H
D000375:Aging / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000503:physiopathology; D006439:Hemodynamics; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D007668:Kidney / Q000503:physiopathology; D007759:Labyrinth Diseases / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D011506:Proteins / Q000235:genetics*
D008565:Membrane Proteins; C065292:Mpv17 protein, mouse; D011506:Proteins