Indoleamine 2, 3-dioxygenase (IDO) increases during renal fibrogenesis and its inhibition potentiates TGF-β 1-induced epithelial to mesenchymal transition

Abstract

BackgroundIndoleamine 2, 3-dioxygenase (IDO) is an immunomodulatory molecule that has been implicated in several biological processes. Although IDO has been linked with some renal diseases, its role in renal fibrosis is still unclear. Because IDO may be modulated by TGF-β1, a potent fibrogenic molecule, we hypothesized that IDO could be involved in renal fibrosis, especially acting in the TGF-β1-induced tubular epithelial-mesenchymal transition (EMT). We analyzed the IDO expression and activity in a model of renal fibrogenesis, and the effect of the IDO inhibitor 1-methyl-tryptophan (MT) on TGF-β1-induced EMT using tubular cell culture.MethodsMale Wistar rats where submited to 7 days of UUO. Non-obstructed kidneys (CL) and kidneys from SHAM rats were used as controls. Masson’s Tricrome and macrophages counting were used to chatacterize the tissue fibrosis. The EMT was analysed though immunohistochemistry and qRT-PCR. Immunohistochemestry in tissue has used to show IDO expression.MDCK cells were incubated with TGF- β1 to analyse IDO expression. Additionally, effects of TGF- β1 and the inhibition of IDO over the EMT process was acessed by immunoessays and scrath wound essay.ResultsIDO was markedly expressed in cortical and medular tubules of the UUO kidneys. Similarly to the immunolocalizaton of TGF- β1, accompanied by loss of e-cadherin expression and an increase of mesenchymal markers. Results in vitro with MDCK cells, showed that IDO was increased after stimulus with TGF-β1, and treatment with MT potentiated its expression. MDCK stimulated with TGF-β1 had higher migratory activity (scratch-wound assay), which was exacerbated by MT treatment.ConclusionsIDO is constitutively expressed in tubular cells and increases during renal fibrogenesis. Although IDO is induced by TGF-β1 in tubular cells, its chemical inhibitor acts as a profibrotic agent.

Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

“…Our results demonstrated that IDO protein expression was markedly increased in UUO mice. This observation is in line with a previous study by Matheus et al, who showed that IDO expression and activity increased in the renal tissue of rats subject to seven days of UUO [11]. Moreover, we and others have reported that IDO activity is elevated in CKD patients, and correlated with disease severity [3,4,[20][21][22][23].…”

Correlation of Indoleamine-2,3-Dioxygenase and Chronic Kidney Disease: A Pilot Study

“…It could be useful to study the levels of IDO in these two stages which could be better for assessing kidney function. Secondly, the sample size in our study was still not large enough although bigger than a previous study [ 9 , 16 ]. But the correlation coefficient of eGFR and IDO was pretty high, and the ROC showed that IDO was a promising biomarker for CKD enhancing the negative relationship between IDO and CKD.…”

“…Mutations in the cystic fibrosis have been reported to have a defect in IDO expression and resulted in intensified fibrosis [ 6 ]. On the contrary, kidney studies revealed elevated expression of IDO in tubules in the unilateral ureteral obstruction model and transforming growth factor- β stimulated MDCK cells [ 9 ] as well as diabetic nephropathy patients [ 10 ]. Our study also revealed increased activity of IDO in CKD patients, especially in CKD stage 5.…”

“…A previous study in systemic sclerosis patients showed elevated levels of Kyn and decreased levels of Trp compared with limited cutaneous patients or healthy controls [ 8 ], suggesting increased levels of IDO. IDO was also significantly expressed in cortical and medulla tubules of the UUO mice [ 9 ] indicating IDO may be associated with kidney fibrosis. Diabetic nephropathy study also showed IDO activity was parallel with the severity of CKD and negatively correlated with estimated glomerular filtration rate (eGFR) [ 10 ].…”

SNAI1 interacts with HDAC1 to control TGF‑β2‑induced epithelial‑mesenchymal transition in human lens epithelial cells

“…TGF-β2 could induce EMT in HLEcs (26). The signaling pathways that are activated in response to TGF-β2 and lead to EMT have primarily been conducted in vitro using NMuMG, MdcK and HacaT cell lines (27)(28)(29)(30). In the present study, EMT in HLEB-3 cells was activated when cells were incubated with TGF-β2, providing new insight for further exploring the potential functional relationship between SNAI1 and HdAc1 in the pathogenesis of PcO and its underlying mechanisms.…”