Comparative proteomic analysis of chief and oxyphil cell nodules in refractory uremic hyperparathyroidism by iTRAQ coupled LC-MS/MS

Publication date: Available online 9 March 2018
Source:Journal of Proteomics
Author(s): Shensen Li, Jianping Mao, Mengjing Wang, Minmin Zhang, Li Ni, Ye Tao, Bihong Huang, Jing Chen
SHPT is one of the most common complications of CKD-MBD. Recent studies indicate that oxyphil cell proliferation is related to SHPT progression, while not inhibited by current treatments. The aim of this study was to analysis the correlation between oxyphil cell and clinical indicators in SHPT, further explore the protein expression differences of oxyphil cell. Among 33 MHD patients, 84.8% patients have one or more oxyphil dominant glands and the overall oxyphil cells proportion was 39.5 ± 16.3%. Univariate correlation and multivariable linear regression analyze showed that oral calcitriol dose and treatment duration were independent indicators of oxyphil cell ratio. Proteomic study shown that mitochondrial protein, protein synthesis, and cell cycle regulation were significantly altered in oxyphil cell nodules. DBP was downregulated in oxyphil nodules on protein level, which may contribute to calcitriol resistance by reducing vitamin D transport. Through KEGG and PPI network analysis, Wnt signaling, TGF-β, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules. Among which, MIF-CUL1 axis were significantly increased. These results suggest that the limitations of vitamin D in SHPT treatment is closely related to oxyphil cell and may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell.SignificanceSecondary hyperparathyroidism in end stage renal patients is one of the major challenges facing nephrology field. Emerging data indicate that oxyphil cell may participant in the pathophysiology of secondary hyperparathyroidism, while both calcimimetics and vitamin D receptor activators treatments are underperformed in control oxyphil cell proliferation. In the present study, we validate that the proliferation of oxyphil cells is associated with calcitriol treatment, and discovered that oxyphil cell nodules is significantly different from chief cells nodules in protein expression of mitochondria, protein synthesis and cell cycle regulation. It is noteworthy that DBP was downregulated in oxyphil nodules on protein level and may therefore participate in the resistance of calcitriol therapy by reduce the vitamin D transport capacity. Wnt signaling, TGF-β, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules, among which, MIF-CUL1 axis may play an important role in the regulation of oxyphil proliferation and calcitriol resistance through ubiquitin mediated proteolysis. These results suggest that calcitriol treatment have limitations in oxyphil cell predominant SHPT, which may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell, and the influence of microenvironment in uremia status may be underlying reason.

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