Pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) activate toll like receptors (TLRs) that stimulate the innate immune system. Immune system activation is linked to blunted renal autoregulatory behavior. Lipopolysaccharide (LPS), a component of the bacterial wall of gram-negative bacteria, is a ligand for TLR4. Preliminary experiments indicates that TLR4 protein expression is increased approximately by 28% (n=2) in small intrarenal arteries after 4 hours of acute LPS treatment versus control. Accordingly, we hypothesize that acute LPS treatment blunts afferent arteriolar autoregulatory behavior through TLR4 activation. Rats received a bolus injection of LPS (1mg/kg I.P.) and kidneys were harvested 4 hours later for juxtamedullary nephron studies. At a perfusion pressure of 100 mmHg, baseline arteriolar diameters in LPS treated kidneys averaged 11.9 ± 0.5μm (n=15) compared to 14.5 ± 0.7μm (n=14) in untreated controls (P < 0.05). Autoregulatory behavior was assessed in these same groups by increasing perfusion pressure in 15 mmHg increments from 65 to 170 mmHg. In control kidneys, afferent arteriolar diameter decreased by 29 ± 5 % (n=6) as perfusion pressure increased from 65 to 170 mmHg. In LPS treated kidneys, afferent arteriolar diameter actually increased by 3 ± 8% (P < 0.05; n=7) over the same pressure range, indicating marked blunting of pressure-induced vasoconstriction. P2 receptors have been implicated in autoregulatory resistance adjustments. Therefore, we assessed afferent arteriolar responsiveness to P2 receptor activation in vitro. In control kidneys, log concentrations of ATP (10-8 - 10-4 mol/L) reduced arteriolar diameter by 4 ± 1, 10 ± 2, 17 ± 4, 26 ± 5, and 32 ± 5% respectively (P < 0.05; n=8). In LPS treated kidneys, ATP reduced arteriolar diameter similarly by 6 ± 1, 11 ± 2, 15 ± 3, 18 ± 4, and 21 ± 5% respectively (P < 0.05; n=8). No significant difference in afferent arteriolar reactivity to ATP was found between the two groups. These data support the hypothesis that TLR4 activation by acute LPS treatment attenuates afferent arteriolar autoregulatory behavior. Accordingly, these data may open novel therapeutic approaches for prevention of inflammatory kidney disease.