The Molecular Basis of Increased Glomerulosclerosis after Blockade of the Renin Angiotensin System in Growth Hormone Transgenic Mice

Autor: Aneeta Patel, Agnes B. Fogo, Iekuni Ichikawa, Liliane J. Striker, Gary E. Striker, E. P. Peten
Rok vydání: 1994
Předmět:
Angiotensin receptor
Captopril
Kidney Glomerulus
Tetrazoles
Angiotensin-Converting Enzyme Inhibitors
Blood Pressure
Kidney
Renin-Angiotensin System
Diabetic nephropathy
Mice
Type IV collagen
chemistry.chemical_compound
Renin
Lymphotoxin-alpha
Genetics (clinical)
biology
Glomerulosclerosis
Focal Segmental
Imidazoles
Organ Size
Extracellular Matrix
Glomerular Mesangium
medicine.anatomical_structure
Gelatinases
Creatinine
Molecular Medicine
Collagen
Research Article
Glomerular Filtration Rate
medicine.medical_specialty
Mice
Transgenic
Angiotensin Receptor Antagonists
Internal medicine
Renin–angiotensin system
Genetics
medicine
Albuminuria
Animals
Collagenases
RNA
Messenger
cardiovascular diseases
Molecular Biology
Base Sequence
business.industry
Body Weight
Glomerulosclerosis
Muscle
Smooth
Angiotensin-converting enzyme
medicine.disease
Actins
Juxtaglomerular Apparatus
Disease Models
Animal
Endocrinology
chemistry
Growth Hormone
biology.protein
business
Thymidine
Zdroj: Molecular Medicine. 1:104-115
ISSN: 1528-3658
1076-1551
DOI: 10.1007/bf03403536
Popis: BACKGROUND: Angiotensin converting enzyme inhibitor (ACEi) therapy delays the onset of renal failure in diabetic nephropathy and inhibits or delays the onset of proteinuria in several animal models. MATERIALS AND METHODS: We examined this question using a transgenic model of chronic glomerulosclerosis caused by an excess production of growth hormone (GH) in which there is progressive glomerular scarring leading to uremia. In addition, since GH mice do not have systemic hypertension or an elevated glomerular filtration rate, we could address the question of whether ACEi or angiotensin II receptor antagonists (AII RA) had an effect on the development of glomerulosclerosis under these conditions. Since excess matrix accumulates in glomerulosclerosis because of alterations in the balance between its synthesis and degradation, we examined the effect of ACEi and AII RA on these parameters. RESULTS: Systemic blood pressure was unaffected by ACEi treatment, but the glomerular filtration rate decreased 85%. ACEi-treated mice had increased mesangial deposition of type I collagen and decreased 105 kD complex collagenase activity. In addition, ACEi-treated GH mice had increased glomerular alpha 1 type I collagen, alpha 1 type IV collagen, and alpha-smooth muscle cell actin mRNAs. No changes were noted in beta actin, or 72 kD metalloproteinase mRNAs. The result of these changes was a net increase in sclerosis. Surprisingly, GH mice treated with ACEi or AngII RA developed marked renal arteriolar lesions. CONCLUSIONS: In some forms of glomerulosclerosis, the lesions develop independently of angiotensin II. Pharmacological inhibition of angiotensin II, in this circumstance, may aggravate the lesions through disregulation of the levels and the balance between glomerular matrix synthesis and degradation.
Databáze: OpenAIRE
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