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- Title
Glomerulosclerosis and Albuminuria in Transgenic Rats due to AT1 Receptor Overexpression in Podocytes.
- Authors
Hoffmann, S.; Podlich, D.; Hänel, B.; Gretz, N.; Kriz, W.
- Abstract
Objective: Angiotensin II (Ang II) is a key regulator of glomerular filtration. Increased Ang II exacerbates progression to end-stage renal disease and inhibition of Ang II actions markedly retards proteinuria and progression to glomerulosclerosis. In addition to hemodynamic effects, pressure independent actions of Ang II are involved that are poorly understood. The podocyte, one of the main players in the progression of chronic renal disease, seems to be a direct target for Ang II. The aim of the present study was to investigate the impact of Ang II type 1 receptors (AT1) receptors on podocytes with respect to structure and function of the glomerular filter. Methods: Transgenic rats (TGR) were developed by pronuclear microinjection of the human AT1 receptor cDNA (1.4 kb) under the regulatory control of the 1.25 kb human nephrin promoter fragment. The podocyte specific transgene expression was verified by in situ hybridization and RT-PCR. The expression levels of the transgenic and endogenous Ang II receptors were analyzed by Northern blot and Receptor binding studies. Systolic blood pressure (BP) was measured by tail-cuff plethysmography. For determination of 24 hr urinary protein and albumin excretion rats were placed into metabolic cages. Structural changes in the kidney were evaluated by light and electron microscopy and quantified by using a damage scoring. Results: Three TGR lines were developed overexpressing the human AT1 receptor specifically in the kidney in the glomerular podocytes. The TGR line with the highest transgene expression level was studied in more detail. A roughly 2 fold overexpression of the human AT1 receptor relative to the endogenous AT1 receptor induced the development of a significant albuminuria in all male TGR. Albuminuria started at 8-15 weeks of age with an albumin excretion of 7 mg/24 hr, which steadily progressed up to 100 mg/24 hr at 32 weeks of age. BP was not elevated in TGR. Already at an age of 5 to 7 weeks, when albumin excretion was still normal, the first structural changes, the ubiquitous formation of pseudocysts at podocytes, were encountered. Foot process effacement and local detachments of podocytes followed more or less simultaneously. This damage progressed to nephron loss via the well known pathway typical for 'classic' focal segmental glomerulosclerosis (FSGS). The structural changes significantly correlated with age (r2 = 0.76), and the urinary albumin excretion (r2 = 0.70). The glomerular volume, podocyte number and the glomerular volume per podocyte in TGR and in wild-type rats were not different. Conclusions: Our data provide direct evidence, that increased AT1 receptor signaling in podocytes leads to protein leakage and structural podocyte damage progressing to FSGS. The well known renoprotective effects of AT1 receptor blockade beyond those derived from lowering blood pressure seem therefore directly mediated by the podocytes.
- Subjects
ALBUMINURIA; CHRONIC kidney failure; GENE expression; GLOMERULAR filtration rate; TRANSGENIC mice; TRANSGENE expression
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p289
- ISSN
1420-4096
- Publication type
Article