| Summary: | 博士 === 國立成功大學 === 臨床醫學研究所 === 105 === Chronic kidney disease (CKD) consisting of renal inflammation and fibrosis is associated with many cardiovascular risk factors, and secondary hyperparathyroidism (SHPT) is one of them. Early growth response-1 (Egr-1) protein is a zinc-finger transcription factor participating in tissue inflammation and fibrosis, but its role in CKD is not fully understood. My PhD research aimed to investigate the potential of Egr-1 and SHPT as therapeutic targets for the treatment of CKD and associated mortality risk. The kidney tissues from animals with tubulointerstitial nephritis and from humans with renal failure both showed increased expression and activation of Egr-1 in renal tubules. Egr-1 deficiency in mice attenuated renal failure via interfering with NF-κB-mediated renal inflammation and transforming growth factor-β-mediated renal fibrosis, but the effect of Egr-1 deficiency on inflammasome was minor. The ex vivo studies using primary cultures of proximal tubular epithelial cells (PTECs) also showed that Egr-1 deficiency suppressed NF-κB pathway and attenuated the responses of PTECs to pro-inflammatory and pro-fibrotic stimulations. These findings suggested the causative role of Egr-1 in renal failure. As for targeting SHPT for the treatment of CKD patients, I studied the association between parathyroidectomy (PTx) and long-term mortality risk in dialysis patients. Histories of receiving radionuclide parathyroid scan were used, for the first time, as a selection criterion to ensure the presence of SHPT in all enrolled cases of a nationwide cohort of dialysis patients. The patients undergoing PTx after scanning had a lower crude mortality rate than the matched patients not undergoing PTx. The analysis of multivariable Cox proportional hazard model showed that PTx was independently associated with a 20% to 25% reduction of all-cause mortality rate. These findings provide minimally biased evidence to support current guidelines that PTx should be recommended for CKD patients with unremitting SHPT. To sum up, my thesis suggested that Egr-1 may serve as a potential therapeutic target for CKD and showed that targeting SHPT with PTx is effective in reducing mortality risk of CKD patients. The study results added to the understanding of pathological relevance of Egr-1 and suggest implications for clinical therapy.
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