[PP.07.24] PLATELET-DERIVED GROWTH FACTOR B: A NOVEL DETERMINANT OF JUXTAGLOMERULAR CELL PHENOTYPIC PLASTICITY?. (September 2017)

• Record Type: Journal Article
• Authors: Martini, A.; Friesema, E.C.H.; Danser, A.H.J.; Reudelhuber, T.L.
• Is Part Of: Journal of hypertension. Volume 35(2017)Supplement 2
• Publication Date: 2017-09
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000523380.68905.f1
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: Renin, a key component in the regulation of blood pressure, is produced by the highly specialized renal juxtaglomerular (JG) cells. These cells may be derived from vascular smooth muscle cells (VSMC) and they can reversibly differentiate in response to certain stimuli. Because these cells rapidly differentiate when removed from the kidney, the biochemical mechanism responsible for this phenotypic plasticity is currently unknown. To overcome this limitation, we quantified gene expression in human renin-producing tumors (reninomas) and subsequently studied the effect of the most promising ligands on renin synthesis in (pro)renin-producing As4.1 cells, which are derived from a mouse JG cell-targeted tumor. Design and method: Transcriptome analysis was performed on four reninomas. The most highly expressed genes common in all reninomas were subsequently used for in situ hybridization in the mouse kidney. This approach yielded 43 genes, from which 12 ligands were selected. As4.1 cells were incubated for 48 hours with conditioned medium derived from human embryonic kidney (HEK) 293 cells transfected for 48 hours with the mouse cDNA encoding these ligands. Subsequently, As4.1 medium, and cell lysate or RNA were collected, and (pro)renin was measured in these samples by enzyme-kinetic assay. Results: Under control conditions, As4.1 cell medium contained predominantly (>95%) prorenin. In contrast, cell lysates contained renin only, at levels corresponding to <1% of the total amount of (pro)renin in the medium (i.e., 161 ± 61 μg angiotensin I/ml.hr, mean ± SEM). Among the tested ligands, only platelet-derived growth factor B (PDGF-B) affected the medium and cellular (pro)renin levels, as well as As4.1 renin gene expression, inducing parallel decreases of 64 ± 5%, 53 ± 10% and 84 ± 5%, respectively. Additionally, PDGF-B-exposed As4.1 cells displayed a more elongated and aligned shape with no apparent alteration in their viability. This was accompanied by a downregulated expression of α-smooth muscle actin (P < 0.01), and an upregulated expression of interleukin-6 (P < 0.0001), suggesting a phenotypic shift from myo-endocrine to inflammatory. No significant changes in the JG cell marker aldo-keto reductase 1B7 (Akr1b7) were observed. Conclusions: PDGF-B might be one of the factors involved in JG cell phenotypic plasticity.