The influence of connexin 45 on renal autoregulation

Abstract

The kidney maintains constant renal blood flow and glomerular filtration rate despite acute changes in renal perfusion pressure (RPP) via renal autoregulation. Renal autoregulation is made up of the myogenic response and the tubuloglomerular feedback (TGF) mechanism, both acting on the afferent arteriole. Both mechanisms have a conducted component, believed to proceed via gap junctions (GJ). These fluid‐filled pores are made up of two connexons, one from each cell, with connexins (Cx) as building blocks. Several Cx isoforms are expressed in the renal vessel wall, including connexin 45 (Cx45), making it a functional syncytium. Disruption of Cx expression and function in the vasculature reduces myogenic response and causes TGF dysregulation, and is associated with hypertension development. The aim of the study was to explore the influence Cx45 has on renal autoregulation.To investigate the TGF mechanism, experiments were performed using the isolated perfused juxtamedullary nephron preparation. Kidneys were isolated from wild type (WT) and smooth muscle cell knockout (KO) Cx45 mice and perfused with a Tyrode's buffer containing BSA and amino acids mixture, at pH 7.4. Local afferent vasoconstriction was induced by electrical pulse stimulation administered via microelectrode, at the glomerular entrance. RPP was kept constant at 95 mmHg and inner afferent arteriolar diameter was measured locally and at upstream sites to evaluate vascular conduction. Responses between WT and KO were compared.To investigate the myogenic response, arteriolar diameter was measured in response to changes in RPP. Experiments were performed in the same setup as previously mentioned, using a stepwise increase in RPP. Perfusion was initiated at 95 mmHg and increased in steps of 20 mmHg until 195 mmHg is reached. Inner afferent arteriolar diameter was measured 100 μm upstream from the glomerulus, and responses between WT and KO were compared. To eliminate the TGF mechanism and isolate only the myogenic response in the kidneys, papillectomy were performed before repeating the same experimental protocol. Responses between WT and KO were compared.To further investigate the influence of Cx45 in the renal vascular function, interlobar arteries from WT and KO mice were isolated and mounted in a pressure myograph. An experimental protocol consisted of stepwise pressure increases of 25 mmHg, starting at 25 mmHg until 175 mmHg is reached. Inner diameter from both WT and KO were measured and compared. In this set‐up no TGF is present.In both WT and KO mice, electrical stimulation at the glomerular pole of the afferent arteriole reduces the diameter at the local site. The conducted vasoconstriction at upstream sites was attenuated in KO mice. The conducted response is observed at 400 μm in the WT mice and 250 μm in the KO. Preliminary myogenic data shows that pressure increases induce a greater afferent vasoconstriction in WT mice and less so in the Cx45 KO. These results suggest that Cx45 may play a role in TGF signaling and myogenic response in the preglomerular vasculature and thus renal autoregulation.Support or Funding InformationThe work is part of the Dynamical Systems Interdisciplinary Network, University of CopenhagenThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.