Lack of Connexins 40 and 45 Reduces Local and Conducted Vasoconstrictor Responses in the Murine Afferent Arterioles

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.

Tubuloglomerular Feedback Synchronization in Nephrovascular Networks

“…[43][44][45][46][47][48] Studies with Cx40-knockout mice have shown the dominant role of Cx40 in the kidney [49][50][51] and systemically. 6,[52][53][54] VSMCs show prominent expression of Cx45 36,55,56 and variable expression of Cx43, mostly in cultured VSMCs. 35 Radial communication from ECs to VSMCs occurs via myoendothelial gap junctions (MEGJs) (Figure 2).…”

Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function

“…Cx37, Cx40, and Cx43 are expressed in endothelial cells (ECs) and smooth muscle cells (SMCs) [12,66,68,75,[78][79][80]. Cx45 has been observed in the SMCs of cerebral vessels [81][82][83][84]. The goal of the cited studies [12,66,68,73,[75][76][77][78][79][80][81][82][83][84] was to evaluate the role of gap junction channels in microcirculation homeostasis.…”

“…Cx45 has been observed in the SMCs of cerebral vessels [81][82][83][84]. The goal of the cited studies [12,66,68,73,[75][76][77][78][79][80][81][82][83][84] was to evaluate the role of gap junction channels in microcirculation homeostasis. However, the direct contribution of Cxs hemichannels to the regulation of the vasomotor tone was not evaluated and is incompletely understood.…”

“…ECs and SMCs are physically divided by the internal elastic lamina in arterioles; these cells are in contact via cell promontories that skewer the internal elastic lamina and match the other cell type at points comprehended as myoendothelial junctions [12,66,68,73,[75][76][77][78][79][80][81][82][83][84]. These points of connection seem to form approvingly specialized subcellular signaling microdomains, and gap junctions located at myoendothelial junctions (i.e., myoendothelial gap junctions) supply an essential pathway for a key regulation of the vasomotor tone through the radial transmission of current and molecules as we described above (i.e., Ca 2+ and small signaling metabolites).…”

Clinical Aspects of Connexins 37, 40, 43, 45 Expression in the Embryonic and Adult Kidneys

“…В сосудах Cx 45 ассоциирован с мРНК α-SMA (α-Smooth muscle actin), а в клубочках -с мРНК PDGFRβ (Platelet-derived growth factor receptor β). Кроме того, имеются данные об экспрессии мРНК Cx 45 интерстициальными фибробластическими клетками [18]. Сведения об экспрессии Сх 45 ренин-секретирующими клетками противоречивы.…”