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The angiotensin receptor neprilysin inhibitor LCZ696 affords superior cardioprotection and renoprotection compared with renin-angiotensin blockade monotherapy, but the underlying mechanisms remain elusive. Herein, we evaluated whether LCZ696 attenuates renal fibrosis by inhibiting ASK1/JNK/p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Rats with UUO were treated daily for 7 days with LCZ696, valsartan, or the selective ATP competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-444217. The effects of LCZ696 on renal injury were examined by assessing the histopathology, oxidative stress, intracellular organelles, apoptotic cell death, and MAPK pathways. H2O2-exposed human kidney 2 (HK-2) cells were also examined. LCZ696 and valsartan treatment significantly attenuated renal fibrosis caused by UUO, and this was paralleled by downregulation of proinflammatory cytokines and decreased inflammatory cell influx. Intriguingly, LCZ696 had stronger effects on renal fibrosis and inflammation than valsartan. UUO-induced oxidative stress triggered mitochondrial destruction and endoplasmic reticulum stress, which resulted in apoptotic cell death; these effects were reversed by LCZ696. Both GS-444217 and LCZ696 hampered the expression of death-associated ASK1/JNK/p38 MAPKs. In H2O2-treated HK-2 cells, LCZ696 and GS-444217 increased cell viability but decreased the production of intracellular reactive oxygen species and MitoSOX and apoptotic cell death. Both agents also deactivated H2O2-stimulated activation of ASK1/JNK/p38 MAPKs. These findings suggest that LCZ696 protects against UUO-induced renal fibrosis by inhibiting ASK1/JNK/p38 MAPK-mediated apoptosis.

Renal fibrosis represents the final common outcome of chronic kidney disease of virtually any etiology. However, the mechanism underlying the evolution of renal fibrosis remains to be addressed. This study sought to clarify whether RIP1-RIP3-mediated necroptosis is involved in renal fibrosis via Wnt3α/β-catenin/GSK-3β signaling in vitro and in a rat model of unilateral ureteral obstruction (UUO). Rats with UUO were administered RIP inhibitors (necrostatin-1 or GSK872) or β-catenin/TCF inhibitor ICG-001 daily for 7 consecutive days. UUO caused significant renal tubular necrosis and overexpression of RIP1-RIP3-MLKL axis proteins, and was accompanied by activation of the NLRP3 inflammasome and renal fibrosis. Oxidative stress caused by UUO was closely associated with endoplasmic reticulum stress and mitochondrial dysfunction, which resulted in apoptotic cell death via Wnt3α/β-catenin/GSK-3β signaling. All of these effects were abolished by an RIP inhibitor (necrostatin-1 or GSK872) or ICG-001. In H2O2-treated HK-2 cells, both RIP inhibitor and ICG-001 decreased intracellular reactive oxygen species production and apoptotic cells, but increased cell viability. Activated Wnt3α/β-catenin/GSK-3β signaling was decreased by either RIP inhibitor or ICG-001. Our findings suggest that RIP1-RIP3-mediated necroptosis contributes to the development of renal fibrosis via Wnt3α/β-catenin/GSK-3β signaling in UUO and may be a therapeutic target for protection against renal scarring of other origins.

The angiotensin receptor neprilysin inhibitor LCZ696 affords superior cardioprotection and renoprotection compared with renin-angiotensin blockade monotherapy, but the underlying mechanisms remain elusive. Herein, we evaluated whether LCZ696 attenuates renal fibrosis by inhibiting ASK1/JNK/p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Rats with UUO were treated daily for 7 days with LCZ696, valsartan, or the selective ATP competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-444217. The effects of LCZ696 on renal injury were examined by assessing the histopathology, oxidative stress, intracellular organelles, apoptotic cell death, and MAPK pathways. H2O2-exposed human kidney 2 (HK-2) cells were also examined. LCZ696 and valsartan treatment significantly attenuated renal fibrosis caused by UUO, and this was paralleled by downregulation of proinflammatory cytokines and decreased inflammatory cell influx. Intriguingly, LCZ696 had stronger effects on renal fibrosis and inflammation than valsartan. UUO-induced oxidative stress triggered mitochondrial destruction and endoplasmic reticulum stress, which resulted in apoptotic cell death; these effects were reversed by LCZ696. Both GS-444217 and LCZ696 hampered the expression of death-associated ASK1/JNK/p38 MAPKs. In H2O2-treated HK-2 cells, LCZ696 and GS-444217 increased cell viability but decreased the production of intracellular reactive oxygen species and MitoSOX and apoptotic cell death. Both agents also deactivated H2O2-stimulated activation of ASK1/JNK/p38 MAPKs. These findings suggest that LCZ696 protects against UUO-induced renal fibrosis by inhibiting ASK1/JNK/p38 MAPK-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Urban traffic is an important source of global CO2 emissions. Uncovering the temporal and structural characteristics can provide scientific support to identify the variation regulation and main subjects of urban traffic CO2 emissions. The road class is one of the most important factors influencing the urban traffic CO2 emissions. Based on the annual traffic field monitoring work in 2014 and the localized MOVES model, this study unravels the temporal variation and structural characteristics of the urban traffic CO2 emissions and conducts a comparative analysis of expressway (5R) and arterial road (DB), two typical classes of urban roads in Beijing. Obvious differences exist in the temporal variation characteristics of the traffic CO2 emissions between the expressway and arterial road at the annual, week and daily scales. The annual traffic CO2 emissions at the expressway (5R, with 47271.15 t) are more than ten times than those of the arterial road (DB, with 4139.19 t). Stronger weekly "rest effect" is observed at the expressway than the arterial road. The daily peak time and duration of the traffic CO2 emissions between the two classes of urban roads show significant differences particular in the evening peak. The differences of the structural characteristics between the two classes of urban roads are mainly reflected on the contribution of the public and freight transportation. Passenger vehicles play a predominant role at both the two classes of urban roads. The public transportation contributed more at DB (24.76%) than 5R (5.47%), and the freight transportation contributed more at 5R (23.41%) than DB (3.49%). The results suggest that the influence of traffic CO2 emissions on the CO2 flux is significant at the residential and commercial mixed underlying urban areas with arterial roads (DB) but not significant at the underlying urban park area with expressway (5R) in this study. The vegetation cover in urban areas have effects on the CO2 reduction. Increasing the design and construction of the green space along the urban roads with busy traffic flow will be an effective way to mitigate the urban traffic CO2 emissions and build the low-carbon cities.

Municipal infrastructure is a fundamental facility for the normal operation and development of an urban city and is of significance for the stable progress of sustainable urbanization around the world, especially in developing countries. Based on the municipal infrastructure data of the prefecture-level cities in China, municipal infrastructure development is assessed comprehensively using a FA (factor analysis) model, and then the stochastic model STIRPAT (stochastic impacts by regression on population, affluence and technology) is examined to investigate key factors that influence municipal infrastructure of cities in various stages of urbanization and economy. This study indicates that the municipal infrastructure development in urban China demonstrates typical characteristics of regional differentiation, in line with the economic development pattern. Municipal infrastructure development in cities is primarily influenced by income, industrialization and investment. For China and similar developing countries under transformation, national public investment remains the primary driving force of economy as well as the key influencing factor of municipal infrastructure. Contribution from urbanization and the relative consumption level, and the tertiary industry is still scanty, which is a crux issue for many developing countries under transformation. With economic growth and the transformation requirements, the influence of the conventional factors such as public investment and industrialization on municipal infrastructure development would be expected to decline, meanwhile, other factors like the consumption and tertiary industry driven model and the innovation society can become key contributors to municipal infrastructure sustainability.

[This corrects the article DOI: 10.1371/journal.pone.0181917.].