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Impairs Renal Autoregulation via Generation of ROS
1 Dorrance Hamilton Research Laboratories, Division of Nephrology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
2 Department of Physiology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: Kumar.Sharma{at}jefferson.edu.
Impaired autoregulation, in chronic kidney disease, can result in elevation of glomerular
capillary pressure and progressive glomerular damage; however, the factors linking
chronic glomerular disorders to impaired autoregulation have not been identified. We
tested the hypothesis that the cytokine most closely associated with progressive
glomerular disease; TGF-
, may also attenuate autoregulation. Kidneys from normal rats
were prepared for videomicroscopy, using the blood perfused juxtamedullary nephron
(JMN) technique. Autoregulatory responses were measured under control conditions and
during superfusion with TGF-1 (10 ng/ml). Control afferent arteriolar diameter
averaged 18.4 ± 1 µm and significantly decreased to 16.3 ± 0.9 and 13.2 ± 0.8 µm at
perfusion pressures of 130 and 160mmHg, respectively. In the presence of TGF-1,
autoregulatory responses were completely blocked. In similar experiments performed
using PDGF-BB (10 ng/ml) and HGF (25 ng/ml), the normal autoregulatory response
was not affected. In vitro studies, using isolated pre-glomerular vascular smooth muscle
cells, revealed that exposure to TGF-1 stimulated a rapid increase in reactive oxygen
species (ROS) that was inhibited by NADPH oxidase inhibitors. In situ studies, with
DHE staining, revealed a marked increase in renal vessel ROS production upon exposure
to TGF-1. Pre-treatment of the juxtamedullary afferent arterioles with Tempol, a ROS
scavenger, or with apocynin, a NADPH oxidase inhibitor, prevented the impaired
autoregulation induced by TGF-1. These data reveal a novel hemodynamic pathway by
which TGF- could lead to progressive glomerular injury by impairing normal renal
microvascular function.
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