All ETDs from UAB

Advisory Committee Chair

Edward Inscho

Advisory Committee Members

Michelle Fanucchi

James George

David Pollock

Jennifer Pollock

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Renal autoregulation is an intrinsic property of afferent arterioles that maintains a stable RBF, glomerular capillary pressure, and GFR, while protecting the glomeruli against fluctuations in arterial pressure. Recently it has been reported that immune system activation and inflammation have been linked to impairment of renal autoregulatory behavior. Evidence suggests that activation of toll-like receptor 4 (TLR4) plays an important role in the progression of AKI and CKD. The contributions of innate immune system activation, TLR4 and renal autoregulatory dysfunction remain unknown. This dissertation explores the novel concept that both acute and chronic TLR4 activation leads to the attenuation of afferent arteriole autoregulatory behavior. Furthermore, it explores the possibility that treatment with competitive antagonist peptide (CAP), a Major Histocompatibility Complex II (MHC II) antagonist, can preserve or restore renal autoregulatory efficiency during chronic renal inflammation. It was found that acute lipopolysaccharide (LPS; 1 mg/kg; i.p.) treatment impairs afferent arteriole autoregulatory behavior. Blockade of TLR4 activation with anti-TLR4 antibody or a TLR4 competitive antagonist, LPS-RS preserved arteriole autoregulatory behavior. Interestingly, P2 purnioceptor function was normal in acute LPS treated rats. Furthermore, scavenging of superoxide with Tempol, restored afferent arteriole autoregulatory behavior in acute LPS treated rats. Additionally, it was found that chronic low-dose LPS (0.1 mg/kg/day; s.q.) treatment for 8 or 14 days impaired afferent arteriole autoregulatory behavior. Inhibition of TLR4 with anti-TLR4 antibody (1 g; i.p.), or chronic co-treatment with Tempol, preserved afferent arteriole autoregulatory behavior in chronic LPS treated rats. Finally, this dissertation showed that co-treatment or intervention with CAP, a MHC II antagonist, preserved and rescued afferent arteriole autoregulatory behavior in chronic 8-day and 14-day LPS treated rats, respectively. Collectively, these data suggest that both acute and chronic stimulation of TLR4 can impair afferent arteriole autoregulatory behavior. Acutely, TLR4-dependent attenuation of renal autoregulatory behavior seems to be through a ROS dependent mechanism. Additionally, chronic TLR4 activation leads to impaired renal autoregulatory behavior through MHC II processing and presentation, and accumulation of ROS. This study establishes a novel mechanism by which TLR4 activation can impair renal autoregulatory behavior.

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