Role of gap junctions in renal vascular conducted response

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The juxtaglomerular apparatus (JGA) is an essential structure in the regulation of renal function and embodies two major functions: tubuloglomerular feedback (TGF) and renin secretion. Both mechanisms function to regulate renal microcirculation, in addition to a plethora of systemic effects. The JGA is a unique structure to study intercellular communication. Intercellular connections, gap junctions (GJ), allow exchange of ions, nutrients, and small signaling molecules between neighboring cells. GJs consist of two connexons, one from each cell, with connexins (Cx) as their building blocks. Several Cx isoforms are expressed in the JGA [1], making the JGA a functional syncytium. Disruption of the signaling pathways in the JGA is associated with reduced TGF response, dysregulation of renin secretion, and hypertension [2,3]. The aim of the study was to determine if reduced intercellular communication affects the conduction of TGF‐induced vasoconstriction in the afferent arteriole.

Experiments were performed using the isolated perfused juxtamedullary nephron preparation. Kidneys were isolated from wild type (WT) and knockout (KO) of both Cx40 and Cx45 mice. Kidneys were perfused with a Tyrodes buffer containing 5% BSA and an amino acid mixture, at pH 7.4. The inner renal surface contains a unique nephron population and allows access to the afferent arteriole. Local afferent vasoconstriction was induced by electrical pulse stimulation (300ms, 90V), administered via 2M NaCl filled microelectrode (0.5–0.8 MΩ) at the glomerular entrance. These electrical stimulations emulate the initiation of vascular TGF responses. Renal perfusion pressure was kept constant at 95 mmHg. Inner afferent arteriolar diameter was measured at the stimulation site (0 μm) and every 50 μm, at distances upstream (up to 450 μm), following a protocol consisting of a 5 min acclimation period, 30 sec baseline, 30 sec electrical pulse stimulation, and 30 sec recovery measurements. Responses between WT and KO of both Cx40 and Cx45 mice were compared.

Preliminary data shows that electrical stimulation at the glomerular pole of the afferent arteriole reduces the diameter in all four groups at the local stimulation sites, with the vasoconstriction effect attenuated at upstream sites. A loss of vasoconstriction in response to stimulation is observed at 200 μm in Cx40 KO mice, and at 250 μm in Cx45 KO mice. In the WT mice, attenuation in the vasoconstriction is observed further upstream, at 450 μm in Cx40 WT mice. In the Cx45 WT mice no attenuation is observed at the measured distance of 300 μm.

These results suggest that both Cx40 and Cx45 may play a significant role in the propagation of the afferent vasoconstriction elicited by electrical stimulation, and thus in the TGF signaling in the JGA.
TidsskriftThe FASEB Journal
Udgave nummerS.1
StatusUdgivet - 2017
BegivenhedExperimental Biology 2017 - Chicago, USA
Varighed: 22 apr. 201726 apr. 2017


KonferenceExperimental Biology 2017

ID: 238375701