Hypertension in an Animal Model of Kidney Disease is not Dependent on the Short‐Term Actions of Endogenous Tumour Necrosis Factor‐α in the SFO

Abstract

Introduction The development of hypertension in the Lewis polycystic kidney (LPK) disease model of kidney disease is caused, in part, by the overactivation of the subfornical organ (SFO). Circulating proinflammatory cytokines, namely tumour necrosis factor-α (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. Methods Urethane anaesthetised Lewis control (n=18 total) and LPK (n=18 total) rats were instrumented to record blood pressure and perform microinjections of TNFRI neutralising antibody (1ng/50nl) or minocycline (0.5µg/50nl), an inhibitor of microglial activation, followed by a GABAa agonist (10mM isoguvacine) into the SFO. Results Exogenous TNFα microinjected into the SFO elicited a significant pressor response in the Lewis control but not the LPK rats (9±2mmHg vs 3±4mmHg peak change from baseline, P=0.0004). Acute inhibition of local TNFα by microinjection of a TNFRI neutralising antibody into the SFO did not reduce mean arterial blood pressure in Lewis control or LPK rats (1±1mmHg vs -1±1mmHg change from baseline, P=0.78). Similarly, acute non-specific blockade of proinflammatory cytokines by microinjection of minocycline in the SFO did not reduce blood pressure in Lewis control or LPK rats (-1±1mmHg vs -1±1mmHg change from baseline, P=0.98). Microinjection of a GABAa agonist into the SFO caused a significant depressor response that was not altered by the pre-treatment with a microinjection of TNFRI neutralising antibody in either strain (P>0.05), demonstrating that pre-treatment did alter the tonic activation of neurons within the SFO. Interestingly, pre-treatment with a microinjection of minocycline increased the tonic activation in the LPK (P=0.04), but not Lewis (P=0.15), as indicated by the increased depressor response to GABAa agonist microinjection. Conclusions Overall, these findings demonstrate that although the hypertension observed in the LPK is sustained by an increase in SFO activity, the short-term control of blood pressure is not dependent on the actions of endogenous TNFα or generalised microglial and neuronal activation by proinflammatory cytokines in the SFO.