NF-κB plays an important role in PG hyperplasia progression. VDR deficiency may be involved in the parathyroid gland hyperplasia through the activation of NF-κB pathway.

No abstract

Secondary hyperparathyroidism (SHPT) in uremic patients characterizes by parathyroid gland (PTG) hyperplasia and parathyroid hormone (PTH) elevation. Previously, we demonstrated that NF-κB activation contributed to parathyroid cell proliferation in chronic kidney disease (CKD) rats. Although vitamin D inhibits inflammation and ameliorates SHPT, the contribution of vitamin D deficiency to SHPT via local NF-κB activation remains to be clarified. PTGs collected from 10 uremic patients with advanced SHPT were used to test the expressions of vitamin D receptor (VDR), NF-κB, and proliferating cell nuclear antigen (PCNA). Freshly excised PTG tissues were incubated for 24 h in vitro with VDR activator (VDRA) calcitriol or NF-κB inhibitor Pyrrolidine Thiocarbamate (PDTC). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to investigate the regulation of PTH transcription by NF-κB. We found higher levels of activated NF-κB and lower expression of VDR in nodular hyperplastic PTGs than in diffuse hyperplasia. In cultured PTG tissues, treatment with VDRA or PDTC inhibited NF-κB activation and PCNA expression, and downregulated preproPTH mRNA and intact PTH levels. ChIP assays demonstrated the presence of NF-κB binding sites in PTH promoter. Furthermore, in luciferase reporter assays, addition of exogenous p65 significantly increased PTH-luciferase activity by 2.4-fold (p<0.01), while mutation of NF-κB binding site at position –908 of the PTH promoter suppressed p65-induced PTH reporter activity (p<0.01). In summary, local NF-κB activation contributes to SHPT and mediates the transcriptional activation of PTH directly in uremic patients. Vitamin D deficiency may be involved in SHPT via the activation of NF-κB pathway.

Mycoplasma pneumoniae infection may induce a systemic hypercoagulable abnormality, like organ embolism and infarction. Indexes of blood coagulation and C-reactive protein (CRP) have been reported different between healthy people and mycoplasma pneumoniae pneumonia (MPP) patients, but this difference in MPP patients with different chest imaging findings has rarely been reported. We performed a retrospective study of 101 children with MPP and 119 controls, combined with radiological examination and blood tests, to compare the blood coagulation and CRP level among MPP children with different chest imaging findings. For the MPP children with different chest imaging findings, there were significant differences in CRP, fibrinogen (FIB) and D-dimer (D-D) levels among subgroups (P = .004, P = .008 and P < .001 respectively). The CRP level in group of interstitial pneumonia was significantly higher than that in groups of bronchopneumonia and hilar shadow thickening (P = .003 and P = .001 respectively). And the FIB and D-D values in group of lung consolidation were significantly higher than that in the other 3 groups (all P < .05). When compared with controls, the white blood cell, CRP, FIB, and D-D levels in MPP children were significantly higher, and the activated partial thromboplastin time and thrombin time levels were significantly lower (all P < .05). Our results showed that CRP level changed most significantly in group of interstitial pneumonia, whereas FIB, D-D levels changed most significantly in the lung consolidation group.

No abstract

<b><i>Background:</i></b> The change of podocyte morphology is a pathologic feature of chronic kidney disease. Several studies have suggested that vitamin D plays a role in the protection of podocytes, but the underlying mechanism remains unclear. <b><i>Methods:</i></b> The effects of paricalcitol on podocyte injury were tested in a puromycin aminonucleoside (PAN)-induced rat model and cultured mouse podocytes. Proteinuria, podocyte foot process (FP) effacement, and the expression of nestin and vitamin D receptor (VDR) were evaluated. VDR-siRNA or plasmids containing VDR-shRNA were transfected into podocytes to silence <i>VDR</i> expression. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to verify the connection between <i>VDR</i> and <i>nestin</i> gene expression. <b><i>Results:</i></b> Paricalcitol significantly alleviated proteinuria and podocyte FP effacement in PAN-induced nephrosis, which was accompanied by increased VDR expression in the glomeruli. Paricalcitol also inhibited PAN-induced nestin overexpression in the glomeruli. In an in vivo study, PAN significantly inhibited VDR protein expression, stimulated nestin protein expression, and resulted in nestin filament derangement in mouse podocytes, while paricalcitol treatment abolished these effects. In contrast, downregulation of VDR resulted in derangement and overexpression of nestin. ChIP assays demonstrated the presence of a vitamin D response element (VDRE) in the <i>nestin</i> promoter, and paricalcitol enhanced the binding of VDR to VDRE. Furthermore, luciferase reporter assays of the <i>nestin</i> promoter fragment showed that paricalcitol effectively repressed nestin reporter gene expression after PAN treatment, and mutation of VDRE abolished this effect. <b><i>Conclusions:</i></b> Paricalcitol directly regulates nestin transcription through the interaction of VDR/VDRE, thereby preventing morphological changes of podocytes in PAN nephropathy.

Parathyroid hormone (PTH) is secreted by the parathyroid glands (PTGs) and is an important hormone regulating mineral metabolism. Previous studies reported that high sodium diet will cause the increase in serum PTH, but the specific mechanism is unknown. Consequently, the present study aims to investigate the effects and mechanisms of high sodium on PTH synthesis and secretion from PTGs. We developed a tissue culture model using normal rat PTGs, discovered that sodium elicited and promoted concentration-dependent and time-dependent PTH secretion. Changes in sodium-associated transporters from PTGs incubated with high sodium were thoroughly examined. Increased expression of sodium-phosphate cotransporter Slc20a1 (also known as PiT-1) was observed. Further tests revealed that PiT-1 activated the NF-κB signaling pathway, resulting in increased IKKβ phosphorylation, IKBα degradation, and increased p65 phosphorylation followed by nuclear entry, which led to increased PTH transcription. Meanwhile, IKKβ phosphorylated SNAP23, promoting exocytosis and eventually led to increased PTH secretion. In conclusion, our findings indicate that PiT-1 plays an important role in the increased secretion and synthesis of PTH directly induced by high sodium under physiological conditions, and may provide a potential therapeutic target for secondary hyperparathyroidism (SHPT).

Background The proximal tubule is the sensing site of sodium and phosphate and the main place for the synthesis and metabolism of 1,25(OH) 2 D 3 . We aimed to investigate the effects of high sodium on the synthesis and function of active vitamin D and local phosphate regulation in proximal tubular epithelial cells. Methods Human proximal tubule epithelial (HK-2) cells were treated with different concentrations of sodium/phosphate. The expression of 1α-OHase and 24-OHase was determined. Liquid chromatography/mass spectrometry (LC/MS) and enzyme-linked immunosorbent assay (ELISA) were used to detect the levels of 1,25(OH) 2 D 3. RNA sequencing and bioinformatics analysis was used to probe into the possible pathways. Chromatin samples were immunoprecipitated with antibodies against parathyroid receptor 1 (PTH1R) and Klotho. Results We found that high sodium decreased the expression of 1,25(OH) 2 D 3 by reducing 1α-OHase and 24-OHase, reduced the expression of PTH1R and Klotho, and increased the intracellular calcium concentration. These effects were reversed by sodium phosphate transporter inhibitor, sodium hydrogen transporter inhibitor, and a chelator of the extracellular calcium, whereas enhanced by ouabain. Vitamin D receptor (VDR) agonists significantly increased the recruitment of VDR to the vitamin D response element (VDRE) of PTH1R and Klotho promoter, thus increasing the expression of PTH1R and Klotho. Conclusions High sodium can decrease the synthesis of active vitamin D in the proximal tubules, affect the gene regulation of 1,25(OH) 2 D 3 /VDR, and significantly reduce the expression of PTH1R and Klotho. It revealed the influence of a high-sodium diet on mineral metabolism and the core role of vitamin D in kidney mineral metabolism.