Renal Afferent Neurons are altered by Lipopolysaccharides (LPS)

Abstract

Sympathetic renal nerve activity (RSNA) is dramatically increased in lipopolycaccharide (LPS)‐incduced SIRS. This might be due to altered properties of renal afferent nerves (RANs), which exert complex neurogenic sympatho‐modulatory and paracrine effects. Hence, we wanted to test the hypotheses that LPS alters the TRPV1 receptor induced CGRP release from RANs in kidney tissue slices and/or the firing patterns and acid induced inward currents in cultured neurons. 1.) Anethetized male Sprague‐Dawley rats were treated with (E.coli O127/B8,20mg/kg IV) while blood pressure (BP), heart rate (HR), RSNA was measured. 2.)Dorsal root ganglion neurons (Th11‐L2) of rats were incubated with LPS (E.coli O127/B8,20mg/l) 12h before patch clamp recordings. Inward currents were assessed during stimulation of TRPV1 and ASICs with protons (pH6,9 and 5,0). Current clamp mode was performed at physiological conditions and after 12h of LPS‐incubation. Neurons were characterized as tonic, i.e. sustained AP firing or phasic, i.e.<5 APs in response to current injections. In an organ bath of kidney slices – incubated with or without LPS ‐ we stimulated TRPV1 receptors with Capsaicin and subsequently measured CGRP content in the organ bath supernatant (ELISA).1.) In vivo measurements showed a strong increase of RSNA (+250%, p<0.05) and HR (+25%, p<0.05) while BP did not change significantly. 2.) Firing patterns and currents induced by acidic superfusion were studied in 246 neurons. Renal neurons (RNs) exhibited in 59% tonic firing pattern under control conditions. The number of neurons with tonic response was significantly reduced by exposure to LPS (59% vs.42%, p<0,05). Under control conditions 70,8% of RNs exhibited both sustained and transient inward currents, whereas 29,2% showed sustained current only. LPS exposure significantly increased sustained, i.e. TRPV1 induced current (−793,18+/−66pA vs.−1224+/−200pA,p<0,05) and transient, i.e. ASICs induced inward current even under subthreshold proton stimulation (pH6,9) which could not be enhanced further by pH5,0. 3. Neurogenic CGRP release from kidney due to TRPV1 stimulation was also significantly increased after LPS incubation (LPS: 58□20 pg/ml, control: 14□2, *p<0.05).LPS altered the properties of neurons with renal axons in a complex way: while the ease of AP production was significantly decreased, the responsiveness to acidic milieu was increased. The TRPV1 induced CGRP release (likely from renal afferent nerves) was also increased.In how far these findings subserve neurogenic alterations in the kidney due to increased sympathetic drive and neural peptide release during experimental sepsis needs further research.