Upregulation of intrarenal angiotensinogen in diabetes

Universidade Federal de São Paulo, Dept Med, Div Nephrol, BR-04023040 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, BR-04023040 São Paulo, BrazilWeb of Scienc

The role of reactive oxygen species in apoptosis of the diabetic kidney

Increased levels of reactive oxygen species (ROS) by hyperglycemia can induce apoptosis of renal cells and diabetic nephropathy. The redox balance in the renal cell seems, therefore, of the utmost importance. ROS-mediated apoptosis may be further aggravated by an inadequate cytoprotective response against ROS. When there are insufficient cytoprotective and ROS scavenging molecules, ROS lead to considerable cellular damage and to a point of no return in apoptosis. Induction of cytoprotective proteins may prevent or attenuate apoptosis, renal cell injury, and finally diabetic nephropathy. Here, we discuss some mechanisms of apoptosis and several strategies that have been probed to ameliorate, or to prevent apoptosis in the diabetic kidney

Analysis and verification of the HMGB1 signaling pathway

Background\ud Recent studies have found that overexpression of the High-mobility group box-1 (HMGB1) protein, in conjunction with its receptors for advanced glycation end products (RAGEs) and toll-like receptors (TLRs), is associated with proliferation of various cancer types, including that of the breast and pancreatic.\ud \ud Results\ud We have developed a rule-based model of crosstalk between the HMGB1 signaling pathway and other key cancer signaling pathways. The model has been simulated using both ordinary differential equations (ODEs) and discrete stochastic simulation. We have applied an automated verification technique, Statistical Model Checking, to validate interesting temporal properties of our model.\ud \ud Conclusions\ud Our simulations show that, if HMGB1 is overexpressed, then the oncoproteins CyclinD/E, which regulate cell proliferation, are overexpressed, while tumor suppressor proteins that regulate cell apoptosis (programmed cell death), such as p53, are repressed. Discrete, stochastic simulations show that p53 and MDM2 oscillations continue even after 10 hours, as observed by experiments. This property is not exhibited by the deterministic ODE simulation, for the chosen parameters. Moreover, the models also predict that mutations of RAS, ARF and P21 in the context of HMGB1 signaling can influence the cancer cell's fate - apoptosis or survival - through the crosstalk of different pathways

Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c‐IAP2 protein in human colon carcinomas

BACKGROUND: High mobility group box 1 (HMGB1) is a non‐histone chromosomal protein implicated in a variety of biologically important processes, including transcription, DNA repair, V(D)J recombination, differentiation, and development. Overexpression of HMGB1 inhibits apoptosis, arguing that the molecule may act as an antiapoptotic oncoprotein. Indeed, increased expression of HMGB1 has been reported for several different tumour types. In this study, we analysed human colon carcinoma for HMGB1 as well as for c‐IAP2 expression levels. c‐IAP2 is an antiapoptotic protein which may be upregulated as a consequence of nuclear factor κB (NFκB) activation via HMGB1. METHODS: A comparative genomic hybridisation (CGH) database comprising 1645 cases from different human tumour types was screened to detect cytogenetic changes at the HMGB1 locus. Immunohistochemical staining of human colon tissue microarrays and tumour biopsies, as well as western blot analysis of tumour lysates, were performed to detect elevated HMGB1 and c‐IAP2 expression in colon carcinomas. The antiapoptotic potential of HMGB1 was analysed by measuring caspase activities, and luciferase reporter assays and quantitative polymerase chain reaction analysis were employed to confirm NFκB activation and c‐IAP2 mRNA upregulation on HMGB1 overexpression. RESULTS: According to CGH analysis, the genomic locus containing the HMGB1 gene was overrepresented in one third (35/96) of colon cancers. Correspondingly, HMGB1 protein levels were significantly elevated in 90% of the 60 colon carcinomas tested compared with corresponding normal tissues evaluable from the same patients. HMGB1 increased NFκB activity and led to co‐overexpression of the antiapoptotic NFκB target gene product c‐IAP2 in vitro. Furthermore, increased HMGB1 levels correlated with enhanced amounts of c‐IAP2 in colon tumours analysed by us. Finally, we demonstrated that HMGB1 overexpression suppressed caspase‐9 and caspase‐3 activity, suggesting that HMGB1 interferes with the apoptotic machinery at the level of apoptosomal caspase‐9 activation. CONCLUSIONS: We identified in vitro a molecular pathway triggered by HMGB1 to inhibit apoptosis via c‐IAP2 induction. Our data indicate a strong correlation between upregulation of the apoptosis repressing HMGB1 and c‐IAP2 proteins in the pathogenesis of colon carcinoma