Hypertension, a major risk factor for cardiovascular disease among US citizens and causes significant endo organ damage due to inflammation, and tissue injury. Exquisite autoregulatory control of renal vascular resistance is essential to protect against hyperbaric trauma and glomerular injury. Loss of autoregulatory control, as occurs in hypertension, increases glomerular capillary pressure and promotes renal injury. Hypertension activates inflammatory cascades that sustain the hypertensive state and accelerate renal injury progression. Anti-inflammatory treatment prevents autoregulatory impairment but a critical barrier to progress with hypertensive renal injury is identification of the inflammatory mechanisms involved. We now provide compelling new evidence identifying toll-like receptor 4 (TLR4) and major histocompatibility complex class II (MHC-II) molecules as mechanistic links between inflammation and autoregulatory dysfunction. The studies proposed address the central hypothesis the TLR4 on renal microvascular cells and on resident MHC-II bearing cells is activated in hypertension, leading to afferent arteriole autoregulatory dysfunction and kidney injury.
Aim 1 will test the hypothesis that chronic TLR4 activation with low dose LPS treatment blunts afferent arteriole autoregulatory behavior. We will use the blood-perfused juxtamedullary nephron preparation to investigate the role of TLR4 signaling on autoregulatory function. Chronic administration of the TLR4 agonist, LPS, anti-TLR4 antibodies or TLR4 antagonists will reveal the role of TLR4 in intact renal microvessels of normotensive rats.
Aim 2 will test the hypothesis that AngII hypertension blunts autoregulatory behavior through mechanisms linked to TLR4 activation. Autoregulatory behavior will be assessed in vitro and in vivo in AngII-infused hypertensive rats with and without chronic administration of LPS, anti-TLR4 antibody or a TLR4 antagonist to establish the role of TLR4 in the renal microvascular dysfunction that occurs in AngII hypertension.
Aim 3 will test the hypothesis that TLR4-mediated loss of autoregulation in AngII hypertension is prevented by targeting MHC-II. A novel CLIP antagonist that ameliorates TLR4-mediated loss of autoregulation will test the efficacy of targeting MHC-II in AngII hypertension. Upon completion of these aims, we will have established that chronic TLR4 activation leads to a decline in renal microvascular autoregulatory capability and that this process is linked to MHC-II immune activation. We further expect that TLR4 activation underlies the renal autoregulatory dysfunction in AngII-induced hypertension through this MHC-II mechanism and contributes to hypertensive renal injury.
Millions of US citizens are hypertensive and can progress to renal injury. While linkage of inflammation with hypertension is recognized, the inflammatory signals involved are unknown. We propose that renal autoregulatory impairment in hypertension involves TLR4 activation. These studies will advance our understanding of the link between TLR4-induced inflammatory cascades and autoregulatory dysfunction.
| Guan, Z; Wang, F; Cui, X et al. (2018) Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles. Acta Physiol (Oxf) 222: |
| Van Beusecum, J P; Zhang, S; Cook, A K et al. (2017) Acute toll-like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour. Acta Physiol (Oxf) 221:204-220 |
| Bosetti, Francesca; Galis, Zorina S; Bynoe, Margaret S et al. (2016) ""Small Blood Vessels: Big Health Problems?"": Scientific Recommendations of the National Institutes of Health Workshop. J Am Heart Assoc 5: |
| Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65 |
| Van Beusecum, Justin; Inscho, Edward W (2015) Regulation of renal function and blood pressure control by P2 purinoceptors in the kidney. Curr Opin Pharmacol 21:82-8 |
| Pandit, Meghana M; Inscho, Edward W; Zhang, Shali et al. (2015) Flow regulation of endothelin-1 production in the inner medullary collecting duct. Am J Physiol Renal Physiol 308:F541-52 |
| Guan, Zhengrong; VanBeusecum, Justin P; Inscho, Edward W (2015) Endothelin and the renal microcirculation. Semin Nephrol 35:145-55 |
| Fellner, Robert C; Guan, Zhengrong; Cook, Anthony K et al. (2015) Endothelin contributes to blunted renal autoregulation observed with a high-salt diet. Am J Physiol Renal Physiol 309:F687-96 |
| Osmond, David A; Zhang, Shali; Pollock, Jennifer S et al. (2014) Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension. Am J Physiol Renal Physiol 306:F619-28 |
| Fellner, Robert C; Cook, Anthony K; O'Connor, Paul M et al. (2014) High-salt diet blunts renal autoregulation by a reactive oxygen species-dependent mechanism. Am J Physiol Renal Physiol 307:F33-40 |
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