Mesenchymal stem cells differentiate into renin-producing juxtaglomerular (JG)-like cells under the control of liver X receptor-alpha.
Renin is a key enzyme for cardiovascular and renal homeostasis and is produced by highly specialized endocrine cells in the kidney, known as juxtaglomerular (JG) cells. The nature and origin of these cells remain as mysteries. Previously, we have shown that the nuclear hormone receptor liver X receptor-alpha (LXRalpha) is a major transcriptional regulator of the expression of renin, c-myc, and other genes involved with growth/differentiation. In this study we test the hypothesis that LXRalpha plays an important role not only in renin expression but also in renin-containing cell differentiation, specifically from the mesenchymal stem cell (MSC), which may be the origin of the JG cell. Indeed, our data demonstrated that LXRalpha activation by its ligands or cAMP stimulated renin gene expression in both murine and human MSCs. Furthermore, sustained cAMP stimulation of murine MSCs overexpressing LXRalpha led to their differentiation into JG-like cells expressing renin and alpha-smooth muscle actin. These MSC-derived JG-like cells contained renin in secretory granules and released active renin in response to cAMP. In conclusion, the activation of LXRalpha stimulates renin expression and induces MSCs differentiation into renin-secreting, JG-like cells. Our results suggest that the MSC may be the origin of the juxtaglomerular cell and provide insight into novel understanding of pathophysiology of the renin-angiotensin system.
Matsushita
Kenichi
K
Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, Durham, North Carolina 27710, USA.
Morello
Fulvio
F
Wu
Yaojiong
Y
Zhang
Lunan
L
Iwanaga
Shiro
S
Pratt
Richard E
RE
Dzau
Victor J
VJ
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D066298:In Vitro Techniques; D007606:Juxtaglomerular Apparatus / Q000166:cytology* / Q000378:metabolism*; D008024:Ligands; D000071518:Liver X Receptors; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology
C541116:ACTA2 protein, human; D000199:Actins; D006888:Hydroxycholesterols; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C544013:alpha-smooth muscle actin, mouse; C003585:22-hydroxycholesterol; D000242:Cyclic AMP; D012083:Renin