Abstract 17937: Relevance of β1-Adrenoceptor-Autoantibodies for Renal Function
Stimulatory antibodies (Abs) targeting the 2nd extracellular loop (ECII) of the β1-adrenergic receptor (β1-AR) induce heart dilatation & failure in rats. Immunized rats develop hypertension within the first 6 months of immunization, which then evolves into DCM. As β1-ARs are not restricted to the heart, but are also highly expressed in the kidney, we hypothesized that the initial hypertensive phenotype may rely on stimulation of renal β1-ARs.
Methods: N=40 Lewis rats were monthly immunized with a β1-ECII/GST fusion protein. Antibody titers and cardiac function were followed every 3 months by ELISA & echocardiography. Plasma renin activity (PRA), serum and 24h urine samples were analysed regularly. Glomerular filtration rate (GFR) was invasively assessed; then the kidneys were harvested and subjected to histological and molecular analysis. Acute effects of the Abs on PRA were investigated by perfusing isolated kidneys with anti-β1-Abs.
Results: Chronic stimulation of the kidneys by ECII-β1-Abs results in an initial decrease in GFR, pointing towards a constringing effect of these Abs on the juxtaglomerular cells. This - as well as direct activation of the β1-ARs located in the juxtaglomerular apparatus - lead to an increase of renin mRNA and PRA levels. After 6 months, renal feedback mechanisms seem to be engaged to compensate these alterations. The effect of the anti-β1-Abs on renin secretion is in accord with our observations made in the experiments with the isolated perfused kidneys.
Moreover, early activation of β1-ARs in the distal tubules by ECII-β1-Abs resulted in a significant increase in sodium reabsorption, which subsequently affects potassium secretion negatively. This would ultimately lead to increased water reabsorption, contributing to the observed hypertensive phenotype. Changes in electrolyte reabsorption noted at later time-points appear to occur secondary to reduced cardiac function.
Although urine albumin and total protein levels slightly increase from the 12 month on, histological analyses revealed no damage of renal tissues.
In conclusion our findings show that, initially, stimulating anti-β1-Abs appear to be able to modulate renal function, which might indirectly contribute to accelerate the development of the DCM phenotype.
- © 2013 by American Heart Association, Inc.