1,25(OH)2D3 treatment attenuates high glucose-induced peritoneal epithelial to mesenchymal transition in mice

Abstract

It has been previously demonstrated that 1,25(OH)2D3 prevents the progression of epithelial to mesenchymal transition (EMT). However, it remains unclear whether 1,25(OH)2D3 has a role in peritoneal EMT stimulated by high glucose (HG) peritoneal dialysis fluid (PDF). The present study was performed to investigate the role of 1,25(OH)2D3 in the progression of EMT in the peritoneal mesothelium. A total of 35 male Kunming mice were randomly assigned into seven groups. In the control group, no diasylate or saline was infused. In the saline group, the mice were intraperitoneally injected with saline every day for 4 weeks. In the vitamin D group, the mice were subjected to intraperitoneal injections of 1 or 5 µg/kg of 1,25(OH)2D3 once weekly (every Monday) for 4 weeks. The peritoneal dialysis (PD) group were intraperitoneally injected with a conventional 4.25% PDF daily for 4 weeks. The vitamin D+PD group were intraperitoneally injected with 4.25% PDF daily and co-treated with 1 µg/kg or 5 µg/kg 1,25(OH)2D3 once weekly, for 4 weeks. The peritoneal morphology and thickness were assessed by hematoxylin and eosin and Masson's trichrome staining. The peritoneal protein level of EMT markers (α-smooth muscle actin, fibronectin and E-cadherin), vitamin D receptor (VDR), B cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein, transforming growth factor (TGF)-β and Smad3 were evaluated by western blot analysis or immunohistochemical staining. Furthermore, apoptosis was assessed using a Caspase-3 activity assay. The results demonstrated that after 4 weeks of intraperitoneal injections in mice, HG-PDF decreased the expression of VDR, promoted EMT and apoptosis, and increased the thickness of the peritoneal membrane. However, 1,25(OH)2D3 treatment attenuated HG-induced EMT and apoptosis, and decreased peritoneal thickness, which may partially occur through inhibition of transforming growth factor TGF-β/Smad pathways via 1,25(OH)2D3 binding to VDR. The present study demonstrated that 1,25(OH)2D3 attenuated HG-induced EMT and apoptosis in the peritoneal mesothelium through TGF-β/Smad pathways. 1,25(OH)2D3 treatment in conjunction with HG dialysate may provide an improved solution to the peritoneal injury in the process of PD.

Reprogramming of Mesothelial-Mesenchymal Transition in Chronic Peritoneal Diseases by Estrogen Receptor Modulation and TGF-β1 Inhibition

“…Oral rapamycin, which inhibits mTOR, has been shown to reduce peritoneal thickening, inflammation, angiogenesis, and lymphangiogenesis by the blockade of HIF-1α, TGF-β1 and VEGF in murine models of PD induced EPS [46]. Other drugs that have been proposed in EPS treatment include mycophenolate mofetil, colchicine, azathioprine, angiotensin converting enzyme inhibitors/angiotensin II receptor blockers, calcitriol, benfotiamine, thalidomide and dipyramidole [46,58,[127][128][129][130]. The use of non-steroidal immunosuppressants (azathioprine, mycophenolate mofetil, rapamycin), with or without glucocorticoids, may improve EPS, but there are no clinical trials and effectiveness is based on case reports [124].…”

“…The activation of vitamin D receptors has been shown to reduce inflammation and fibrosis in EPS and also acute/chronic pancreatitis [130,157]. This is related to the inhibition of TGF-β1/SMAD signaling by genomic competition, and the blockade of NF-κB activation and p65/p50 nuclear translocation.…”

Antioxidant Supplementation in Renal Replacement Therapy Patients: Is There Evidence?

“…In PD patients, the data regarding the effect of vitamin D analogues on OS are scarce and only derived from experimental studies. In vitro as well as in vivo studies in mice showed that the active form of vitamin D inhibited accumulation of free radicals and glycoxidation and therefore might preserve the peritoneum homeostasis, through amelioration of OS status [107–109].…”

Vitamin D Receptor: A Novel Therapeutic Target for Kidney Diseases

“…Vitamin D analogs can suppress matrix-producing myofibroblast activation by upregulating the expression of anti-fibrotic hepatocyte growth factor in renal interstitial fibroblasts [ 123 ]. In human peritoneal mesothelial cells, inhibitory effects of VDR agonists on EMT have also been reported [ 124 , 125 ].…”