Abstract
Connexins (Cxs) are membrane-spanning proteins which enable flow of information important for kidney homeostasis. Changes in their spatiotemporal patterning characterize blood vessel abnormalities and chronic kidney diseases (CKD). We analysed spatiotemporal expression of Cx37, Cx40, Cx43 and Cx45 in nephron and glomerular cells of developing, postnatal kidneys, and nephrotic syndrome of the Finnish type (CNF) by using immunohistochemistry, statistical methods and electron microscopy. During kidney development, strong Cx45 expression in proximal tubules and decreasing expression in glomeruli was observed. In developing distal nephron, Cx37 and Cx40 showed moderate-to-strong expression, while weak Cx43 expression gradually increased. Cx45/Cx40 co-localized in mesangial and granular cells. Cx43 /Cx45 co-localized in podocytes, mesangial and parietal epithelial cells, and with podocyte markers (synaptopodin, nephrin). Different Cxs co-expressed with endothelial (CD31) and VSMC (α –SMA) markers in vascular walls. Peak signalling of Cx37, Cx43 and Cx40 accompanied kidney nephrogenesis, while strongest Cx45 signalling paralleled nephron maturation. Spatiotemporal Cxs patterning indicate participation of Cx45 in differentiation of proximal tubules, and Cx43, Cx37 and Cx40 in distal tubules differentiation. CNF characterized disorganized Cx45 expression in proximal tubules, increased Cx43 expression in distal tubules and overall elevation of Cx40 and Cx37, while Cx40 co-localized with increased number of interstitial myofibroblasts.
Highlights
During normal human kidney development, the uretheric bud induces the nearby metanephric mesenchyme to transform into metanephric cup cells, which than undergo through several developmental stages, including the renal vesicle stage, S-body and capillary loop stages, subsequently leading to mature nephron and glomeruli formation
Connexins are transmembrane proteins that form gap junctions, which in the kidney tissue primarily contribute to renal haemodynamics, as they mostly localize in the walls of blood vessels
Strong expression of Cx45 displayed decreasing course in glomeruli of developing kidneys, while its strong expression in proximal tubules continued into postnatal period
Summary
During normal human kidney development, the uretheric bud induces the nearby metanephric mesenchyme to transform into metanephric cup cells, which than undergo through several developmental stages, including the renal vesicle stage, S-body and capillary loop stages, subsequently leading to mature nephron and glomeruli formation. Expression of different Cxs in tubular nephron cells and glomerular cells has been mostly analysed in rat and mice postnatal kidneys, but rarely during kidney development. Kidney glomeruli are structures which harbor several cells population and glomerular blood vessels, which display expression of different Cxs. Studies on Cxs expression in glomerular endothelial cells showed contradicting results[24,25,26]. During normal EMT of human kidney stem cell cultures Cx43 expression gradually decreased[35]
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