Based on these data, we conclude that the Fas- and TNFR1-mediated apoptotic pathways are directly involved in the pathogenesis of cisplatin-induced RTC death process.

Objective Lupus nephritis, which shows various histologic patterns, is a serious complication of systemic lupus erythematosus (SLE). We previously demonstrated the importance of Th1 cell–mediated immune response in patients with diffuse proliferative lupus nephritis (DPLN). The aim of this study was to examine the relationship between the peripheral blood Th1/Th2 balance and the intrarenal immune response. Methods The Th1:Th2 ratio in peripheral blood was measured by intracellular staining for cytokines with flow cytometry. Immunohistochemical analysis of renal biopsy specimens was performed to clarify the characterization of local infiltrating cells in 3 groups of subjects: SLE patients with World Health Organization (WHO) class IV nephritis (DPLN) (group I; n = 13), SLE patients with WHO class V nephritis (group II; n = 9), and patients with minor glomerular lesions (group III; n = 7). In addition, the histologic activity index and chronicity index were evaluated and correlated with the Th1:Th2 ratio. Results Immunohistochemical studies showed higher numbers of CD68+ macrophages, CD3+ T cells, and interferon‐γ–positive cells in group I than in groups II or III. Renal tissues from patients in group I also showed up‐regulation of expression of osteopontin and CD40, with a small number of infiltrating T cells expressing interleukin‐4. Overall, the Th1:Th2 ratio in group I patients (SLE with DPLN) was high and correlated significantly with the histologic activity index, but not with the chronicity index. Conclusion We have identified a predominance of Th1‐type response in both peripheral and renal tissues of patients with DPLN, suggesting that the peripheral blood Th1:Th2 ratio directly reflects the local histopathologic findings. In patients with lupus nephritis, the peripheral blood Th1:Th2 ratio could be useful as a parameter that reflects the renal histologic activity or the strength of the local Th1 response.

The reduced expression of p21 and p27, in a VDR-dependent manner, is a major pathogenic factor for a nodular parathyroid gland growth.

No abstract

We have recently demonstrated the direct involvement of the death receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell (RTC) death. Reactive oxygen species are thought to be a major cause of cellular damage in such injury. The aim of this study was to examine the mechanism through which antioxidants ameliorate cisplatin-induced RTC death, with special emphasis on death receptor-mediated apoptotic pathways. Cisplatin was added to cultures of normal rat kidney (NRK52E) cells or injected in rats. NRK52E cells and rats were also treated with dimethylthiourea (DMTU), a hydroxyl radical scavenger. We then examined the mRNA levels of death ligands and receptors, caspase-8 activity, cell viability, cell death, renal function, and histological alterations. RT-PCR indicated cisplatin-induced upregulation of Fas, Fas ligand, and TNF-alpha mRNAs and complete inhibition by DMTU in vitro and in vivo. Cisplatin increased caspase-8 activity of NRK52E cells, and DMTU prevented such activation. Exposure to cisplatin reduced viability of NRK52E cells, examined by WST-1 assay, and increased apoptosis and necrosis of the cells, examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and fluorescence-activated cell sorter analysis. DMTU abrogated cisplatin-induced changes in cell viability and apoptosis and/or necrosis. Cisplatin-induced renal dysfunction and histological damage were also prevented by DMTU. DMTU did not hinder cisplatin incorporation into RTCs. Our results suggest that antioxidants can ameliorate cisplatin-induced acute renal failure through inactivation of the death receptor-mediated apoptotic pathways.