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Connexins and the Kidney
Sponsored by APS Renal Section

Several isoforms of connexin (Cx) junctional proteins have been identified in a variety of tissues where they play a role in intercellular communication. In the kidney, Cx30, Cx37, Cx40, Cx43 and Cx45 have been identified in the vasculature, glomerular mesangium, and in tubule segments, but their function is largely unknown. Emerging understanding of the gap-junctional proteins and new tools for their investigation now offer the opportunity to explore the vital role that Cx molecules may play in regulating renal blood flow, the filtration process, renin release, and tubular reabsorption. The myoendothelial junction in the afferent arteriole is one of the exciting areas of current research. It is evident that gap-junctional communication may be closely linked to overall vascular physiology and that Cx40 is involved in the control of vasomotor tone, as evidenced by its deletion inducing hypertension and irregular vasomotion. The occurrence of hypertension in the Cx40 knockout mice is consistent with the reduced density of Cx40 endothelial gap junction plaques in spontaneously hypertensive rats. Also, Cx40 was found between afferent arteriolar endothelial cells and renin-secreting juxtaglomerular cells and it’s expression was up-regulated during renovascular hypertension in the rat. Thus, there is excellent reason to suppose that intercellular communication mediated by Cx40 may play a role in the regulation of blood pressure by the renal renin-angiotensin system. Dr. Holstein-Rathlou is an expert in physiological expression and function of vascular gap-junctional communication in the afferent arteriole. In addition, there is increasing evidence that intercellular communication between cells of the juxtaglomerular apparatus involves an ATP release-mediated calcium wave that regulates contractile function as well as renin secretion. This is largely based on work from Dr. Oite’s laboratory who also demonstrated that phosphorylation of one of the most ubiquitous isoforms, Cx43 in mesangial cells is important in the regulation and modulation of gap junctional function. Apart from the classic gap junction between two cells, Cx proteins can form large, non-selective ion channels on one cell’s surface. These hemichannels are permeable to a variety of small signaling molecules (calcium, IP3) and other ligands (nucleotides, ATP) and function in purinergic paracrine signaling in many cell types. It remains to be shown what physiological mechanisms regulate hemichannel function, but a recent work from Dr. Peti-Peterdi’s laboratory has identified Cx hemichannels in the distal nephron. Localization of Cx30 at the apical membrane of distal tubule segments (mainly in intercalated cells) highly correlates with the known expression of ATP degrading enzymes and P1 and P2 purinergic receptors. This suggests that Cx hemichannels may be involved in paracrine regulation of tubular function, such as sodium reabsorption, chloride secretion and perhaps more complex renal functions such as pressure natriuresis. Availability of Cx knockout animal models will help to clarify the roles what Cx molecules play in kidney function. Dr. Willecke is a world-renowned expert in the field of gap junctional proteins and his laboratory has generated a number of genetic animal models that will help shed light on connexin function in the kidney.