We showed that increased expression of
complement 3 (C3) induces dedifferentiation of mesenchymal cells and epithelial mesenchymal transition, which activate the local renin-angiotensin system (RAS) that contributes to cardiovascular and renal remodeling in spontaneously hypertensive rats (SHRs). In the present study, to investigate contributions of C3 to the development of the pathogenesis of
hypertension, we evaluated the formation of
renin-producing cells and roles of C3 in
renin generation during differentiation of primary bone marrow-mesenchymal stem cells (MSCs) from C57BL/6 mice, Wistar-Kyoto (WKY) rats, and SHRs to smooth muscle cells (SMCs) with transforming growth factor-β1. The expression of
renin transiently increased with increases in
transcription factor liver X receptor α (LXRα), and expression of C3 and Krüppel-like
factor 5 (KLF5) increased during differentiation of MSCs from C57BL/6 mice, WKY rats, and SHRs to SMCs. Exogenous C3a stimulated
renin and LXRα expression accompanied by nuclear translocation of LXRα. C3a receptor antagonist
SB290157 suppressed
renin and LXRα expression, with inhibition of nuclear translocation of LXRα during the differentiation of mouse MSCs to SMCs. The expression of C3 and KLF5 was significantly higher in the differentiated cells from SHRs compared with the cells from WKY rats during differentiation.
Renin-producing cells were formed during differentiation of MSCs to SMCs, and
renin generation was observed in undifferentiated SMCs, in which transient expression of
renin in the differentiated cells with lower differentiation stage was stronger from SHRs than that from WKY rats. Expression and nuclear localization of LXRα in the differentiated cells from SHRs were stronger than that from WKY rats. C3 was important in forming and maintaining this undifferentiated state of SMCs from MSCs to generate
renin with increases in
transcription factor LXRα and KLF5. Increases in C3 expression maintain the undifferentiated state of SMCs from MSCs to generate
renin that activates RAS and contributes to the pathogenesis of
hypertension in SHRs.