Key result
In a rat model of renal failure, a uremia-inducing diet caused early macrophage accumulation, osteoblast marker expression, and extracellular matrix modifications in the aortic valve before calcification occurred.
In a rat model of renal failure, inflammatory and osteoblastic changes in the aortic valve occur early and downregulate before calcification becomes apparent, suggesting a narrow therapeutic window for medical intervention.
Early macrophage changes may offer prevention targets in uremic valve disease; hypothesis-generating and leaves open human translation.
BACKGROUND: Aortic valve calcification (AVC) secondary to renal failure (RF) is an inflammation-regulated process, but its pathogenesis remains unknown. We sought to assess the cellular processes that are involved in the early phases of aortic valve disease using a unique animal model of RF-associated AVC. METHODS: Aortic valves were obtained from rats that were fed a uremia-inducing diet exclusively for 2, 3, 4, 5, and 6 weeks as well as from controls. Pathological examination of the valves included histological characterization, von Kossa staining, and antigen expression analyses. RESULTS: After 2 weeks, we noted a significant increase in urea and creatinine levels, reflecting RF. RF parameters exacerbated until the Week 5 and plateaued. Whereas no histological changes or calcification was observed in the valves of any study group, macrophage accumulation became apparent as early as 2 weeks after the diet was started and rose after 3 weeks. By western blot, osteoblast markers were expressed after 2 weeks on the diet and decreased after 6 weeks. Collagen 3 was up-regulated after 3 weeks, plateauing at 4 weeks, whereas collagen 1 levels peaked at 2 and 4 weeks. Fibronectin levels increased gradually until Week 5 and decreased at 6 weeks. We observed early activation of the ERK pathway, whereas other pathways remained unchanged. CONCLUSIONS: We concluded that RF induces dramatic changes at the cellular level, including macrophage accumulation, activation of cell signaling pathway and extracellular matrix modification. These changes precede valve calcification and may increase propensity for calcification, and have to be investigated further.
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Shuvy et al. (2015) studied Renal failure-induced aortic valve disease (n=60). High-adenine and high-phosphate diet vs. Normal chow was evaluated on Early cellular alterations in the aortic valve before calcification. In a rat model of renal failure, a uremia-inducing diet caused early macrophage accumulation, osteoblast marker expression, and extracellular matrix modifications in the aortic valve before calcification occurred.
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