Abstract
The juxtaglomerular apparatus (JGA) is an essential structure in the regulation of renal function. The JGA embodies two major functions: tubuloglomerular feedback (TGF) and renin secretion. TGF is one of the mechanisms mediating renal autoregulation. It is initiated by an increase in tubular NaCl concentration at the macula densa cells. This induces a local afferent arteriolar vasoconstriction and a conducted response that can be measured several 100 μm upstream from the juxtaglomerular segment. This spread of the vasomotor response into the surrounding vasculature likely plays a key role in renal autoregulation, and it requires the presence of gap junctions, intercellular pores based on connexin (Cx) proteins. Several Cx isoforms are expressed in the JGA and in the arteriolar wall. Disruption of this communication pathway is associated with reduced TGF, dysregulation of renin secretion, and hypertension. We examine if the absence of Cx40 or Cx45, expressed in the endothelial and vascular smooth muscle cells respectively, attenuates afferent arteriolar local and conducted vasoconstriction. Afferent arterioles from wildtype and Cx-deficient mice (Cx40 and Cx45) were studied using the isolated perfused juxtamedullary nephron preparation. Vasoconstriction was induced via electrical pulse stimulation at the glomerular entrance. Inner afferent arteriolar diameter was measured locally and upstream to evaluate conducted vasoconstriction. Electrical stimulation induced local vasoconstriction in all groups. The local vasoconstriction was significantly smaller when Cx40 was absent. The vasoconstriction decreased in magnitude with increasing distance from the stimulation site. In both Cx40 and Cx45 deficient mice, the vasoconstriction conducted a shorter distance along the vessel compared to wild-type mice. In Cx40 deficient arterioles, this may be caused by a smaller local vasoconstriction. Collectively, these findings imply that Cx40 and Cx45 are central for normal vascular reactivity and, therefore, likely play a key role in TGF-induced regulation of afferent arteriolar resistance.
Highlights
The juxtaglomerular apparatus (JGA) is a specialized structure, formed by the afferent and efferent arteriole, thick limb of the ascending loop of Henle, and mesangial cells
The response, encompasses the entire afferent arteriole, the distal part of the interlobular artery, and travels into the afferent arterioles of neighboring nephrons (Peti-Peterdi, 2006; Marsh et al, 2009). This indicates that the vasoconstrictor signal is conducted within the vascular wall most likely through gap junctions (GJs) coupling endothelial cells (ECs) to ECs, vascular smooth muscle cells (VSMCs) to VSMCs, and ECs to VSMCs
Body weights were significantly higher in Cx40 wildtype (Cx40 WT) mice (33.1 ± 1.3 g) compared to Cx40 knockout (Cx40 KO) mice (27.9 ± 1.7 g, p = 0.04) and in Cx45 WT mice (27.4 ± 1.3 g) compared to
Summary
The juxtaglomerular apparatus (JGA) is a specialized structure, formed by the afferent and efferent arteriole, thick limb of the ascending loop of Henle, and mesangial cells. The response, encompasses the entire afferent arteriole, the distal part of the interlobular artery, and travels into the afferent arterioles of neighboring nephrons (Peti-Peterdi, 2006; Marsh et al, 2009) This indicates that the vasoconstrictor signal is conducted within the vascular wall most likely through gap junctions (GJs) coupling ECs to ECs, VSMCs to VSMCs, and ECs to VSMCs. GJs are fluid-filled pores that allow the movement of small molecules and current between neighboring cells. Previous studies in these mice show that Cx45 plays a role in the propagation of VSMC calcium waves and in TGF (Hanner et al, 2008; Møller et al, 2020) This calcium signaling may be one mechanism by which Cx45 affects vascular conducted responses. We explore the roles of Cx40 and Cx45 in the conduction of vasoconstrictor responses to electrical pulse stimulation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
