Open AccessSDF ‐1α (Stromal Cell‐Derived Factor 1α) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen
Author(s) -
Jackson Edwin K.,
Zhang Yumeng,
Gillespie Delbert D.,
Zhu Xiao,
Cheng Dongmei,
Jackson Travis C.
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.007253
Subject(s) - medicine , endocrinology , stromal cell , fibrosis , cardiac fibrosis , receptor , muscle hypertrophy , microbiology and biotechnology , biology
Background Activated cardiac fibroblasts ( CF s), preglomerular vascular smooth muscle cells ( PGVSMC s), and glomerular mesangial cells ( GMC s) proliferate, cause hypertrophy, and produce collagen; in this way, activated CF s contribute to cardiac fibrosis, and activated PGVSMC s and GMC s promote renal fibrosis. In heart and kidney diseases, SDF ‐1α (stromal cell‐derived factor 1α; endogenous CXCR 4 [C‐X‐C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF ‐1α/ CXCR 4 axis activates CF s, PGVSMC s, or GMC s. Methods and Results Here we investigated whether SDF ‐1α activates CF s, PGVSMC s, and GMC s to proliferate, hypertrophy, or produce collagen. DPP4 (dipeptidyl peptidase 4) inactivates SDF ‐1α and previous experiments show that growth‐promoting peptides have greater effects in cells from genetically‐hypertensive animals. Therefore, we performed experiments in the absence and presence of sitagliptin ( DPP 4 inhibitor) and in cells from normotensive Wistar–Kyoto rats and spontaneously hypertensive rats. Our studies show (1) that spontaneously hypertensive and Wistar–Kyoto rat CF s, PGVSMC s, and GMC s express CXCR 4 receptors and DPP 4 activity; (2) that chronic treatment with physiologically relevant concentrations of SDF ‐1α causes concentration‐dependent increases in the proliferation (cell number) and hypertrophy ( 3 H‐leucine incorporation) of and collagen production ( 3 H‐proline incorporation) by CF s, PGVSMC s, and GMC s; (3) that sitagliptin augments these effects of SDF ‐1α; (4) that interactions between SDF ‐1α and sitagliptin are greater in spontaneously hypertensive rat cells; (5) that CXCR 4 antagonism ( AMD 3100) blocks all effects of SDF ‐1α; and (6) that SDF ‐1α/ CXCR 4 signal transduction likely involves the RACK 1 (receptor for activated C kinase 1)/Gβγ/PLC (phospholipase C)/PKC (protein kinase C) signaling complex. Conclusions The SDF ‐1α/ CXCR 4 axis drives proliferation and hypertrophy of and collagen production by CF s, PGVSMC s, and GMC s, particularly in cells from genetically hypertensive animals and when DPP 4 is inhibited.