Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease characterized by the progressive development of renal cysts with further need for effective therapy. Here our aim was to investigate the effect of Ganoderma triterpenes (GT) on the development of kidney cysts. Importantly, GT attenuated cyst development in two mouse models of ADPKD with phenotypes of severe cystic kidney disease. Assays for tubulogenesis showed that GT promoted epithelial tubule formation in MDCK cells, suggesting a possible effect on epithelial cell differentiation. The role of GT in regulating key signaling pathways involved in the pathogenesis of PKD was further investigated by immune blotting. This showed that GT specifically downregulated the activation of the Ras/MAPK signaling pathway both in vitro and in vivo without detectable effect on the mTOR pathway. This mechanism may be involved in GT downregulating intracellular cAMP levels. Screening of 15 monomers purified from GT for their effects on cyst development indicated that CBLZ-7 (ethyl ganoderate C2) had a potent inhibitory effect on cyst development in vitro. Additionally, like GT, CBLZ-7 was able to downregulate forskolin-induced activation of the Ras/MAPK pathway. Thus, GT and its purified monomer CBLZ-7 may be potential therapeutic regents for treating ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disease that still lacks effective therapy. Repulsive guidance molecule b (RGMb), a co-receptor for bone morphogenetic proteins (BMPs) and a ligand for neogenin, is expressed in renal tubular epithelial cells. Previous studies showed that RGMb plays negative roles in several types of tumors and prevents the immune system from over activation. The present study was designed to explore the effects of RGMb in ADPKD development. We found that expression of RGMb in kidney was less in PKD mice than wild-type mice. With stimulation of 8-bromo-cAMP, RGMb-null embryonic kidneys had greater cyst index, though their ureteric bud branched less than wild-type mice at E13.5. Postnatal RGMb-null kidneys showed interstitial hyperplasia and decreased tubular structures, especially in the boundary area of renal cortex and medulla. RGMb overexpression dramatically inhibited cyst development and promoted tubulogenesis in MDCK cells grown in 3D collagen gels. Biochemical analysis showed increased p-Smad1/5/8 and decreased p-ERK in RGMb-overexpressing MDCK cells, suggesting modulated BMP signaling. Specific inhibition of p-Smad1/5/8 by LDN193189 reversed the suppression of RGMb on MDCK cyst model. These results reveal RGMb as a novel regulator for ADPKD by promoting renal tubule branching and regulating BMP signaling pathway. Elevating RGMb and enhancing p-Smad1/5/8 are promising new strategies to treat ADPKD.

Background Previous work found that urea accumulation in urothelial cells caused by urea transporter B knockout led to DNA damage and apoptosis that contributed to the carcinogenesis. The purpose of this study is to explore the potential connection between high urinary urea concentration and the bladder disorders. Methods A high protein diet rat model was conducted by feeding with 40 % protein diet. In-silico modeling and algorithm, based on the results of microarray and proteomics from the bladder urothelium, were used for the reconstruction of accurate cellular networks and the identification of novel master regulators in the high-protein diet rat model. Pathway and biological process enrichment analysis were used to characterize predicted targets of candidate mRNAs/proteins. The expression pattern of the most significant master regulators was evaluated by qPCR and immunohistochemistry. Results Based on the analysis of different expressed mRNAs/proteins, 15 significant ones (CRP, MCPT2, MCPT9, EPXH2, SERPING1, SRGN, CDKN1C, CDK6, CCNB1, PCNA, BAX, MAGEB16, SERPINE1, HSPA2, FOS) were highly identified and verified by qPCR and immunohistochemistry. They were involved in immune and inflammatory response, cell cycle arrest, apoptosis and pathways in cancer. These abnormally activated processes caused the bladder interstitial congestion and inflammatory infiltrates under the thinner urothelium, cell desquamation, cytoplasm vacuolization, nucleus swelling and malformation in the high-protein diet group. Conclusions We provided evidences that high urinary urea concentration caused by high-protein diet might be a potential carcinogenic factor in bladder.

排斥导向分子(repulsive guidance molecule,RGM)家族包含RGMa、RGMb和RGMc三个成员.RGMb在神经、生殖、免疫系统及肾脏、肺、肌肉等重要器官均有表达,并可通过多种途径调节胚胎发育、免疫系统活性、细胞间黏附、肿瘤发生、损伤修复等重要生理过程.RGMb主要参与RGMb-neogenin-Rho信号通路和BMP信号通路,最近发现的PD-L2-RGMb结合作用提示以RGMb为中心的细胞信号网络与功能调节极为复杂.该文将以RGMb为重点,对与其相关的信号通路、生理功能调节及研究进展加以介绍.

Objective To establish an effective and stable rat model of skin-infection for evaluating the therapeutic effects of topical anti-infection drugs.Methods SD rats were subcutaneously injected with cyclophosphamide to induce immunosuppression,and then surgical incisions were made on both sides of the spine.The rat model of skin-infection was established by applying methicillin-resistant Staphylococcus aureas suspension to the incisions for two consecutive days,and evaluated by analyzing infection status,pathological changes and healing time.Results The development of pyogenic infection was detected in all of the rats.Compared with the non-cyclophosphamide treated group,the cyclophosphamide treated group showed a more severe infection both from the visual inspection and the microscopic observation,moreover,its healing time was delayed more than 10 days.Conclusion The skin-infection model was successfully established in immunosuppressed rats induced by cyclophosphamide,which could be applicable to the efficacy evaluation of anti-infection drugs for external use on skin infection.