Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats.
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.
Fredersdorf
Sabine
S
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. sabine.fredersdorf@klinik.uni-regensburg.de
Weil
Joachim
J
Ulucan
Coskun
C
Birner
Christoph
C
Büttner
Roland
R
Schubert
Thomas
T
Böger
Carsten A
CA
Debl
Kurt
K
Muders
Frank
F
Riegger
Günter A
GA
Luchner
Andreas
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D009320:Atrial Natriuretic Factor / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008859:Microscopy, Polarization / Q000379:methods; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy* / Q000503:physiopathology; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D012084:Renin-Angiotensin System / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
C479877:AVE 7688; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001786:Blood Glucose; D006575:Heterocyclic Compounds, 3-Ring; D011480:Protease Inhibitors; D014280:Triglycerides; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D017257:Ramipril