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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.

journal of the american heart association

SDF ‐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