Indiana University-Purdue University Indianapolis (IUPUI) / Diabetic Kidney Disease (DKD) is a major complication of diabetes. Incomplete understanding of its molecular mechanisms is highlighted by the limited treatments options. We hypothesized that inhibition of protective endogenous mechanisms plays major role in the pathogenesis of DKD. While renoprotection is mediated by cyclic nucleotides (cAMP and cGMP), phosphodiesterases (PDEs) lead to cyclic nucleotide degradation. Our investigation focused on the role of calcium/calmodulin activated PDE1 in DKD. Three isoforms of PDE1 are differentially expressed in vascular smooth muscle cells, renal tubular epithelial cells, podocytes, and mesangial cells. We used highly potent and selective PDE1 inhibitor LY1 to explore systemic hemodynamic and local renal role of PDE1. LY1 reduced systolic and diastolic blood pressure in normotensive and spontaneously hypertensive rats. Renal protection with PDE1 inhibition was tested in mouse model of DKD, featuring a combination of diabetes, nephron loss and arterial hypertension. In this model, a PDE1 inhibitor caused a significant improvement in renal function as evident by significant reduction of albuminuria, serum creatinine and several urine biomarkers of inflammation and injury. Histopathological analysis revealed substantial improvement in the pathology of DKD in the treated group that was associated with the reduction of gene expression related to inflammation and fibrosis. Thus, we revealed the role of calcium activated PDE1 in DKD. However, the source of calcium in this context remained obscure. Our bioinformatics analysis pointed out that calcium channel TRPC6 is likely to be involved. Further in vitro studies demonstrated that TRPC6 activation induced apoptosis in human mesangial cells and isolated rat glomeruli, which was attenuated by both TRPC6 and PDE1 inhibition, thereby suggesting a functional coupling between TRPC6 (as a source of calcium) and PDE1 activation. Moving upstream, we showed that several systemic risk factors of DKD (angiotensin II, endothelin 1 and glucose) activated TRPC6 in a different manner, through generation of either reactive oxygen species or diacylglycerol. The computational modeling to relate human transcriptomic and phenotype data demonstrated the pre-clinical findings of renal benefit upon PDE1 inhibition is translatable in human. Taken together, our results suggest mechanistic link among systemic risk factors, TRPC6, calcium flux and PDE1 activation in pathogenesis of DKD. As a corollary, PDE1 inhibition leads to direct and indirect renoprotective effects.

京都大学 / 新制・課程博士 / 博士(農学) / 甲第24650号 / 農博第2533号 / 新制||農||1096(附属図書館) / 学位論文||R5||N5431(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 太田 毅, 教授 横井 伯英, 教授 舟場 正幸 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Secure information exchanges over cyberspace is on the increase due to the convergence of wireless and mobile access technologies in all businesses. Accordingly, with the proliferation of diverse multicast group service subscriptions that are possible to co-exist within a single broadband network, there is also huge demand by the mobile subscribers to ubiquitously access these services over high speed broadband using their portable devices. Likewise, the Network Providers (NPs) invest hugely in infrastructure deployment to disseminate these services efficiently and concomitantly. Therefore, cyber security in any business is obligatory to restrict access of disseminated services to only authorised personnel. This becomes a vital requirement for a successful commercialisation of exchanged group services. The standard way to achieve cyber security in a wireless mobile multicast communication environment is through confidentiality using Group Key Management (GKM).The existing GKM schemes for secure wireless multicast from literature only target single group service confidentiality; however, the adoption of multiple group service confidentiality in them involve inefficient management of keys that induce huge performance overheads unbearable for real time computing. Therefore, a novel authenticated GKM scheme for multiple multicast group subscriptions known as slot based multiple group key management (SMGKM) is proposed. In the SMGKM, the handovers move across diverse decentralised clusters of homogeneous or heterogeneous wireless access network technologies while participating in multiple group service subscriptions. Unlike the conventional art, the SMGKM advances its security by integrating location based authentication and GKM functions. Both functions are securely offloaded from the Domain Key Distributor (DKD) to the intermediate cluster controllers, Area Key Distributors (AKDs), in a distributed fashion, using the proposed location based authenticated membership list (SKDL). A significant upgrade of fast handoff performance with reduced performance overheads of the SMGKM scheme is achieved. The developed numerical analysis and the simulation results display significant resource economy in terms of reduced rekeying transmission, communication bandwidth and storage overheads while providing enhanced security. The performance of the SMGKM in a high speed environment is also evaluated and has demonstrated that SMGKM outperforms the previous work. Finally, the SMGKM correctness against various attacks is verified using BAN logic, the eminent tool for analysing the widely deployed security protocols. The security analysis demonstrates that SMGKM can counteract the security flaws and redundancies identified in the chosen related art.

Secure information exchanges over cyberspace is on the increase due to the convergence of wireless and mobile access technologies in all businesses. Accordingly, with the proliferation of diverse multicast group service subscriptions that are possible to co-exist within a single broadband network, there is also huge demand by the mobile subscribers to ubiquitously access these services over high speed broadband using their portable devices. Likewise, the Network Providers (NPs) invest hugely in infrastructure deployment to disseminate these services efficiently and concomitantly. Therefore, cyber security in any business is obligatory to restrict access of disseminated services to only authorised personnel. This becomes a vital requirement for a successful commercialisation of exchanged group services. The standard way to achieve cyber security in a wireless mobile multicast communication environment is through confidentiality using Group Key Management (GKM).The existing GKM schemes for secure wireless multicast from literature only target single group service confidentiality; however, the adoption of multiple group service confidentiality in them involve inefficient management of keys that induce huge performance overheads unbearable for real time computing. Therefore, a novel authenticated GKM scheme for multiple multicast group subscriptions known as slot based multiple group key management (SMGKM) is proposed. In the SMGKM, the handovers move across diverse decentralised clusters of homogeneous or heterogeneous wireless access network technologies while participating in multiple group service subscriptions. Unlike the conventional art, the SMGKM advances its security by integrating location based authentication and GKM functions. Both functions are securely offloaded from the Domain Key Distributor (DKD) to the intermediate cluster controllers, Area Key Distributors (AKDs), in a distributed fashion, using the proposed location based authenticated membership list (SKDL). A significant upgrade of fast handoff performance with reduced performance overheads of the SMGKM scheme is achieved. The developed numerical analysis and the simulation results display significant resource economy in terms of reduced rekeying transmission, communication bandwidth and storage overheads while providing enhanced security. The performance of the SMGKM in a high speed environment is also evaluated and has demonstrated that SMGKM outperforms the previous work. Finally, the SMGKM correctness against various attacks is verified using BAN logic, the eminent tool for analysing the widely deployed security protocols. The security analysis demonstrates that SMGKM can counteract the security flaws and redundancies identified in the chosen related art.