Ps-B05-7: Hypertension in a Model of PKD Is Not Dependent on the Short-Term Actions of Tumour Necrosis Factor-a in the Sfo

Abstract

Objective:The development of hypertension in the Lewis polycystic kidney (LPK) disease model of kidney disease is caused, in part, by neuronal overactivity in the subfornical organ (SFO). Circulating proinflammatory cytokines, namely TNFα, are suggested to act in the central nervous system to produce an increase in neuronal excitability. As circulating cytokines are increased in kidney disease, we hypothesised that TNFα acts on the SFO to increase neuronal activity, therefore contributing to the development of hypertension in this animal model.Design and Methods:Urethane anaesthetised Lewis control (n = 23 total) and LPK (n = 18 total) animals were instrumented to record blood pressure and perform microinjections of TNFα (1–300pg/50nl), TNFα receptor 1 (TNFRI) neutralising antibody (1ng/50nl) or minocycline (0.5 μg/50nl), an inhibitor of microglial activation.Results:Exogenous TNFα microinjected into the SFO elicited a significant pressor response in the Lewis control but not the LPK animals (9 ± 2 mmHg vs -1 ± 3 mmHg, Lewis vs LPK peak change from baseline, P = 0.04). Acute inhibition of actions of local TNFα via administration of TNFRI neutralising antibody in the SFO did not reduce mean arterial blood pressure in Lewis control or LPK animals (1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.59). Acute blockade of the actions of all proinflammatory cytokines on microglia via microinjection of minocycline in the SFO did not reduce blood pressure in Lewis control or LPK animals (-1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.11). Prior microinjection of TNFRI neutralising antibody into the SFO abolished the pressor response observed upon microinjection of TNFα in Lewis rats (9 ± 2 mmHg vs 1 ± 1 mmHg, TNFα vs TNFα after TNFRI Ab peak change from baseline, P = 0.01), whereas prior microinjection of minocycline into the SFO only attenuated the pressor response observed upon TNFα microinjection in Lewis rats (9 ± 2 mmHg vs 3 ± 1 mmHg, TNFα vs TNFα after Minocycline peak change from baseline, P = 0.04)Conclusions:Overall, these findings demonstrate that although hypertension observed in the LPK is sustained by an increase in SFO activity, the short-term control of mean arterial blood pressure activity is not dependent on the actions of endogenous TNFα or generalised microglial activation by proinflammatory cytokines in the SFO.