Lack of connexin 40 decreases the calcium sensitivity of renin-secreting juxtaglomerular cells
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The so-called calcium paradoxon of renin describes the phenomenon that exocytosis of renin from juxtaglomerular cells of the kidney is stimulated by lowering of the extracellular calcium concentration. The yet poorly understood effect of extracellular calcium on renin secretion appears to depend on the function of the gap junction protein connexin 40 (Cx40) in renin-producing cells. This study aimed to elucidate the role of Cx40 for the calcium dependency of renin secretion in more detail by investigating if Cx40 function is really essential for the influence of extracellular calcium on renin secretion, if and how Cx40 affects intracellular calcium dynamics in renin-secreting cells and if Cx40-mediated gap junctional coupling of renin-secreting cells with the mesangial cell area is relevant for the influence of extracellular calcium on renin secretion. Renin secretion was studied in isolated perfused mouse kidneys. Calcium measurements were performed in renin-producing cells of microdissected glomeruli. The ultrastructure of renin-secreting cells was examined by electron microscopy. We found that Cx40 was not essential for stimulation of renin secretion by lowering of the extracellular calcium concentration. Instead, Cx40 increased the sensitivity of renin secretion response towards lowering of the extracellular calcium concentration. In line, the sensitivity and dynamics of intracellular calcium in response to lowering of extracellular calcium were dampened when renin-secreting cells lacked Cx40. Disruption of gap junctional coupling of renin-secreting cells by selective deletion of Cx40 from mesangial cells, however, did not change the stimulation of renin secretion by lowering of the extracellular calcium concentration. Deletion of Cx40 from renin cells but not from mesangial cells was associated with a shift of renin expression from perivascular cells of afferent arterioles to extraglomerular mesangial cells. Our findings suggest that Cx40 is not directly involved in the regulation of renin secretion by extracellular calcium. Instead, it appears that in renin-secreting cells of the kidney lacking Cx40, intracellular calcium dynamics and therefore also renin secretion are desensitized towards changes of extracellular calcium. Whether the dampened calcium response of renin-secreting cells lacking Cx40 function results from a direct involvement of Cx40 in intracellular calcium regulation or from the cell type shift of renin expression from perivascular to mesangial cells remains to be clarified. In any case, Cx40-mediated gap junctional coupling between renin and mesangial cells is not relevant for the calcium paradoxon of renin secretion.
KeywordsConnexin 40 Renin Calcium juxtaglomerular cells Calcium paradoxon
The expert technical assistance provided by Ramona Steppan and by Robert Götz is gratefully acknowledged.
- 2.Betsholtz C, Lindblom P, Bjarnegard M, Enge M, Gerhardt H, Lindahl P (2004) Role of platelet-derived growth factor in mesangium development and vasculopathies: lessons from platelet-derived growth factor and platelet-derived growth factor receptor mutations in mice. Curr Opin Nephrol Hypertens 13(1):45–52. https://doi.org/10.1097/00041552-200401000-00007 CrossRefPubMedGoogle Scholar
- 4.Chadjichristos CE, Scheckenbach KE, van Veen TA, Richani Sarieddine MZ, de Wit C, Yang Z, Roth I, Bacchetta M, Viswambharan H, Foglia B, Dudez T, van Kempen MJ, Coenjaerts FE, Miquerol L, Deutsch U, Jongsma HJ, Chanson M, Kwak BR (2010) Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion. Circulation 121(1):123–131. https://doi.org/10.1161/CIRCULATIONAHA.109.867176 CrossRefPubMedGoogle Scholar
- 5.Czogalla J, Schweda F, Loffing J (2016) The mouse isolated perfused kidney technique. J Vis Exp 117. https://doi.org/10.3791/54712
- 13.Glenn ST, Jones CA, Pan L, Gross KW (2008) In vivo analysis of key elements within the renin regulatory region. Physiol Genomics 35(3):243–253. https://doi.org/10.1152/physiolgenomics.00017.2008 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Haefliger JA, Krattinger N, Martin D, Pedrazzini T, Capponi A, Doring B, Plum A, Charollais A, Willecke K, Meda P (2006) Connexin43-dependent mechanism modulates renin secretion and hypertension. J Clin Invest 116(2):405–413. https://doi.org/10.1172/JCI23327 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Jobs A, Schmidt K, Schmidt VJ, Lubkemeier I, van Veen TA, Kurtz A, Willecke K, de Wit C (2012) Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension. Hypertension 60(6):1422–1429. https://doi.org/10.1161/HYPERTENSIONAHA.112.201194 CrossRefPubMedGoogle Scholar
- 21.Kurtz A, Penner R (1989) Angiotensin II induces oscillations of intracellular calcium and blocks anomalous inward rectifying potassium current in mouse renal juxtaglomerular cells. Proc Natl Acad Sci U S A 86(9):3423–3427. https://doi.org/10.1073/pnas.86.9.3423 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Kurtz L, Schweda F, de Wit C, Kriz W, Witzgall R, Warth R, Sauter A, Kurtz A, Wagner C (2007) Lack of connexin 40 causes displacement of renin-producing cells from afferent arterioles to the extraglomerular mesangium. J Am Soc Nephrol 18(4):1103–1111. https://doi.org/10.1681/ASN.2006090953 CrossRefPubMedGoogle Scholar
- 26.Peart WS, Quesada T, Tenyi I (1977) The effects of EDTA and EGTA on renin secretion. Br J Pharmacol 59(2):247–252. https://doi.org/10.1111/j.1476-5381.1977.tb07486.x CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Wagner C, de Wit C, Kurtz L, Grunberger C, Kurtz A, Schweda F (2007) Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res 100(4):556–563. https://doi.org/10.1161/01.RES.0000258856.19922.45 CrossRefPubMedGoogle Scholar
- 39.Wagner C, Jobs A, Schweda F, Kurtz L, Kurt B, Lopez ML, Gomez RA, van Veen TA, de Wit C, Kurtz A (2010) Selective deletion of Connexin 40 in renin-producing cells impairs renal baroreceptor function and is associated with arterial hypertension. Kidney Int 78(8):762–768. https://doi.org/10.1038/ki.2010.257 CrossRefPubMedPubMedCentralGoogle Scholar