Upregulation of Thymidine Phosphorylase in Chronic Glomerulonephritis and Its Role in Tubulointerstitial Injury

Abstract

Chronic tubulointerstitial injury (CTI), commonly a sequel to chronic glomerulonephritis (CGN), is associated with the proliferation of new blood vessels. Angiogenesis is an essential process in chronic inflammation, and is controlled by a number of angiogenic factors including thymidine phosphorylase (TP). Knowledge of TP in renal disease is still rudimentary, and its role in CGN has not been explored. We analyzed the expression of TP by RTPCR, immunohistology and in situ hybridization in 20 human kidneys with CGN. To evaluate the degree of angiogenesis, we counted the microvessel density (MVD). MVD was significantly higher in all categories of CGN, between 19.7 ± 7.7 and 58.9 ± 7.5, compared to control value, 12.7 ± 5.0 (p< 0.05). MVD was increased in areas of abundant mononuclear cell infiltration with minimal interstitial fibrosis, and decreased or absent in areas of marked fibrosis. There was a significant correlation between MVD and interstitial fibrosis (p < 0.0001). TP mRNA was upregulated for all categories of CGN. TP was strongly expressed by mononuclear inflammatory cells and in most atrophic tubules. Each MVD and interstitial volume was significantly correlated with both the number of TP+ mononuclear cells and TP+ tubular cells, respectively (p < 0.0001). We have demonstrated an upregulation of TP and increase in MVD in areas of CTI in a variety of CGN. The up-regulation of TP may contribute to angiogenesis, which may play a critical role in the progression of interstitial fibrosis in CGN.

Implications of TP-positive CAFs as a possible inducer of bone invasion in the pathogenesis of oral squamous cell carcinoma

“…Moreover, we also found that, similar to cancer cells, rhTP can promote the proliferation and invasion abilities of CAFs in vitro. A similar promoting role of TP on interstitial brosis in glomerulonephritis was also reported in a previous study (41). Bone resorption occurred more frequently in PDX mouse models in the TP + CAFs group than in the group without TP + CAFs.…”

Valproic Acid Induces Endothelial-to-Mesenchymal Transition-Like Phenotypic Switching

“…Furthermore, VPA has been shown to demonstrate anti-cancer activity in breast cancer via induction of TP or thymidine phosphorylase expression ( Terranova-Barberio et al, 2016 ). The up-regulation of TP contributes to angiogenesis, which may also play a critical role in the progression of fibrosis ( Wang et al, 2006 ). Interestingly, in our qPCR array, we also observed significantly increased expression of TP in ECs following VPA treatment.…”

The dual role of thymidine phosphorylase in cancer development and chemotherapy

“…40,41 Furthermore, TP is upregulated in chronic glomerulonephritis (a renal disease characterized by inflammation of the glomeruli) where it probably plays a critical role in the progression of interstitial fibrosis. 42 Moreover, TP is expressed in atherosclerosis. Macrophages, foam cells, and giant cells from both aortic and coronary plaques were found to be immunoreactive for this angiogenic factor, suggesting that TP may play a role in the pathogenesis of atherosclerosis.…”

“…Reumatoid arthritis [44][45][46][47][48][49][50] Atherosclerosis 43 Psoriasis 38,39 Inflammatory bowel disease 40,41 Chronic glomerulonephritis 42 MNGIE [51][52][53][54][55][56][57][58] deficiency in skeletal muscle leading to mitochondrial disorders characterized by hypertrophic cardiomyopathy and encephalopathy. 61 Thus, more investigations are needed to clarify the exact role of TP deficiency in MNGIE development.…”