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Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats.
- Source :
-
Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2007 Apr; Vol. 375 (2), pp. 95-103. Date of Electronic Publication: 2007 Mar 01. - Publication Year :
- 2007
-
Abstract
- Inhibition of the renin angiotensin aldosterone system (RAAS) produces protective effects on cardio-renal injury in type 2 diabetes. Vasopeptidase inhibitors (VPI) represent a new pharmacological tool, acting by simultaneous inhibition of the RAAS and neutral endopeptidase. We examined the effects of chronic VPI on renal function and morphology in experimental type 2 diabetes as compared to angiotensin converting enzyme inhibition (ACE-I). Zucker diabetic fatty rats aged 13 weeks were treated with either VPI (AVE7688, ZDF-VPI, n = 8) or ACE-I (Ramipril, ZDF-ACE-I, n = 7) or placebo (ZDF, n = 8). Heterozygous rats served as non-diabetic controls (Ctr, n = 8). Both treatments led to a similar decrease in blood pressure. After 10 weeks of treatment, ZDF developed marked albuminuria. The latter was significantly attenuated in ZDF-VPI as compared to ZDF and ZDF-ACE-I. Renal histology revealed a significant expansion in the glomerular tuft area in all ZDF groups. However, expression of glomerular desmin, which has been recognized as a sensitive marker of early podocyte damage, was significantly increased in ZDF as compared to Ctr. Desmin was reduced in ZDF-VPI but not in animals treated with ACE-I. There was a correlation between albumin excretion and desmin-positive glomerular area. In experimental type 2 diabetes, albuminuria correlates to podocyte damage. These hallmarks of diabetic nephropathy are attenuated by VPI to a greater extent than by ACE-I alone. These findings suggest that podocyte damage is an early critical step in the progression of diabetic nephropathy, and that VPI is a promising pharmacological tool in the treatment of diabetic renal disease.
- Subjects :
- Angiotensin-Converting Enzyme Inhibitors pharmacology
Angiotensin-Converting Enzyme Inhibitors therapeutic use
Animals
Antihypertensive Agents pharmacology
Antihypertensive Agents therapeutic use
Atrial Natriuretic Factor blood
Blood Glucose metabolism
Blood Pressure drug effects
Diabetes Mellitus, Experimental blood
Diabetes Mellitus, Experimental physiopathology
Heterocyclic Compounds, 3-Ring pharmacology
Heterocyclic Compounds, 3-Ring therapeutic use
Male
Microscopy, Polarization methods
Podocytes pathology
Protease Inhibitors therapeutic use
Proteinuria physiopathology
Ramipril therapeutic use
Rats
Rats, Zucker
Renin-Angiotensin System drug effects
Triglycerides blood
Weight Gain drug effects
Diabetes Mellitus, Experimental drug therapy
Neprilysin antagonists & inhibitors
Podocytes drug effects
Protease Inhibitors pharmacology
Proteinuria drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0028-1298
- Volume :
- 375
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Naunyn-Schmiedeberg's archives of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17333128
- Full Text :
- https://doi.org/10.1007/s00210-007-0147-9