Cyclooxygenase 2 promotes parathyroid hyperplasia in ESRD.

Hyperplasia of the PTG underlies the secondary hyperparathyroidism (SHPT) observed in CKD, but the mechanism underlying this hyperplasia is incompletely understood. Because aberrant cyclooxygenase 2 (COX2) expression promotes epithelial cell proliferation, we examined the effects of COX2 on the parathyroid gland in uremia. In patients with ESRD who underwent parathyroidectomy, clusters of cells within the parathyroid glands had increased COX2 expression. Some COX2-positive cells exhibited two nuclei, consistent with proliferation. Furthermore, nearly 78% of COX2-positive cells expressed proliferating cell nuclear antigen (PCNA). In the 5/6-nephrectomy rat model, rats fed a high-phosphate diet had significantly higher serum PTH levels and larger parathyroid glands than sham-operated rats. Compared with controls, the parathyroid glands of uremic rats exhibited more PCNA-positive cells and greater COX2 expression in the chief cells. Treatment with COX2 inhibitor celecoxib significantly reduced PCNA expression, attenuated serum PTH levels, and reduced the size of the glands. In conclusion, COX2 promotes the pathogenesis of hyperparathyroidism in ESRD, suggesting that inhibiting the COX2 pathway could be a potential therapeutic target.

Procyanidin B2 suppresses hyperglycemia-induced renal mesangial cell dysfunction by modulating CAV-1-dependent signaling.

The dysfunction of renal mesangial cells (MCs) is a hallmark of diabetic kidney disease (DKD), which triggers glomerulosclerosis leading to end-stage renal disease. Procyanidin B2 (PB2), the main component of proanthocyanidin, is well known for its antioxidant and anti-inflammatory effects; however, it remains unclear as to whether it has protective effects on DKD. The present study investigated the protective effect of PB2 against hyperglycemia-induced renal MC dysfunction in mouse SV40-Mes13 (Mes13) cells. The Mes13 cells were treated with or without PB2 under HG conditions. Cell proliferation was assessed using an MTT assay and oxidative stress was assessed by examining intracellular ROS generation and H2O2 production. The changes in extracellular matrix accumulation- and cellular inflammation-related proteins were measured by western blot analysis, ELISA and immunofluorescence analysis. The results showed that PB2 treatment markedly attenuated hyperglycemia-induced cell proliferation, oxidative stress, extracellular matrix accumulation and cellular inflammation in Mes13 cells, which was accompanied by an inactivation of redoxosomes, TGF-ß1/SMAD and IL-1ß/TNF-α/NF-κB signaling pathways. The present study also demonstrated that hyperglycemia upregulated and activated caveolin-1 (CAV-1), whereas PB2 treatment potently reversed this effect. In accordance, CAV-1 overexpression abolished the protective effects of PB2 against hyperglycemia in Mes13 cells, indicating that the cytoprotective effect of PB2 was CAV-1-dependent. These findings form the basis of the potential clinical applications of PB2 in the treatment of DKD.

TNFα up-regulates COX-2 in chronic progressive nephropathy through nuclear accumulation of RelB and NF-κB2.

OBJECTIVE: The pathogenesis of progressive nephropathies involves inflammatory factors. The inhibition of cyclooxygenase-2 (COX-2) can limit renal damage and inflammation. However, the mechanism of up-regulation of COX-2 in nephropathy is poorly defined. MATERIALS AND METHODS: Here we found that tumor necrosis factor alpha (TNFα) was involved in expression of COX-2 in normal rat kidney (NRK) cell line. RESULTS: TNFα stimulated COX-2 production in a time-dependent manner in NRK cells by inducing nuclear accumulation of RelB and nuclear factor kappa B2 (NF-κB2) and their association with COX-2 gene promoter. Depletion of IκB-inducing kinase alpha, a positive regulator of activation of p100 processing to active p52, attenuated TNFα-induced COX-2 production. Furthermore, TNFα induced COX-2 production and nuclear import in anti-thymocyte serum (ATS) nephropathy. DISCUSSION AND CONCLUSION: These data suggest that TNFα-RelB/p52 pathway may be involved in the early stages of renal damage, in part by stimulating COX-2 and inflammatory responses.