Fasting Blood Glucose: A Mediator of the Association between Estimated Glomerular Filtration Rate and Arterial Stiffness in Japanese Population with Decreased Kidney Function.

INTRODUCTION: Low estimated glomerular filtration rate (eGFR) is associated with an increased risk of arterial stiffness in participants with kidney damage. It is uncertain whether this association is due to eGFR itself or is mediated by the eGFR-associated increases in fasting blood glucose (FBG). METHOD: The cross-sectional study included 865 Japanese participants with decreased kidney function, whose eGFR was less than 90 mL/min/1.73 m2, and recruited individuals who received medical healthcare. The mediating variable was FBG, with eGFR as the independent variable and brachial-ankle pulse wave velocity (baPWV) as the dependent variable. A mediation analysis was used to evaluate the mediating effect of FBG on the association between eGFR and arterial stiffness. RESULTS: The mean age of the participants was 51.69 ± 9.25 years old, with 65.90% individuals being male. The mean values for FBG, eGFR, and baPWV were 5.46 ± 0.79 mmol/L, 68.83 ± 10.05 mL/min/1.73 m2, and 1,423.50 ± 247.78 cm/s, respectively. The mediation analysis revealed that eGFR had a significant direct effect on baPWV (ß = -25.68 95% CI: -46.42, -7.45), and that FBG played a partial mediating role in the indirect effect of eGFR on baPWV (ß = -3.54 95% CI: -11.88, -0.079). Mediation analysis showed that 12.10% of the effect of eGFR on risk of arterial stiffness was mediated through FBG. CONCLUSION: The study indicated that there is a mediating relationship between eGFR and FBG in people with decreased kidney function, which is associated with the risk of arterial stiffness. Therefore, the importance of FBG as a mediator should be acknowledged and taken into consideration.

Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction.

BACKGROUND: Hypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)-dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown. METHODS: A mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance. RESULTS: By 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice. CONCLUSIONS: 5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.

Adipocytes initiate an adipose-cerebral-peripheral sympathetic reflex to induce insulin resistance during high-fat feeding.

The underlying mechanism by which amassing of white adipose tissue in obesity regulates sympathetic nerve system (SNS) drive to the tissues responsible for glucose disposal, and causes insulin resistance (IR), remains unknown. We tested the hypothesis that high-fat (HF) feeding increases afferent impulses from white adipose tissue that reflexively elevate efferent nerve activity to skeletal muscle (SM) and adipose tissue to impair their local glucose uptake. We also investigated how salt-intake can enhance IR. HF-fed rats received a normal salt (0.4%) or high salt (4%) diet for 3 weeks. High-salt intake in HF fed rats decreased insulin-stimulated 2-deoxyglucose uptake by over 30% in white adipose tissue and SM, exacerbated inflammation, and impaired their insulin signaling and glucose transporter 4 (Glut4) trafficking. Dietary salt in HF fed rats also increased the activity of the adipose-cerebral-muscle renin-angiotensin system (RAS) axes, SNS, and reactive oxygen species (ROS). Insulin sensitivity was reduced by 32% in HF rats during high-salt intake, but was improved by over 62% by interruption of central RAS and SNS drive, and by over 45% by denervation or deafferentation of epididymal fat (all P<0.05). Our study suggest that a HF diet engages a sympathetic reflex from the white adipose tissue that activates adipose-cerebral-muscle RAS/ROS axes and coordinates a reduction in peripheral glucose uptake. These are all enhanced by salt-loading. These findings provide new insight into the role of a reflex initiated in adipose tissue in the regulation of glucose homeostasis during HF feeding that could lead to new therapeutic approaches to IR.

Urinary angiotensinogen: an indicator of active antineutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: One of the major challenges in improving the management of antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) is the lack of a disease-specific indicator for histological lesions and disease activity. Here we tested the utility of urinary angiotensinogen (UAGT) as a biomarker of renal disease activity in ANCA-GN. METHODS: A prospective, two-stage cohort study was performed in ANCA-GN patients. In Stage I, UAGT was measured at the time of renal biopsy in 69 patients from two centers (test set) and 25 patients from two other centers (validation set). In Stage II, UAGT was monitored in 50 subjects in the test set for 24 months. RESULTS: In Stage I, UAGT significantly increased in ANCA-GN patients, correlating well with cellular crescents formation and active interstitial inflammation. Patients with crescentic ANCA-GN exhibited the highest UAGT compared with other histopathological classes of ANCA-GN. After multivariable adjustment, the highest quartile of UAGT, compared with the lowest quartile, associated with a 6-fold increased risk of crescentic ANCA-GN. For predicting crescentic ANCA-GN, UAGT [area under the receiver operating characteristics curve (AUC) = 0.88] outperformed albuminuria (AUC = 0.73) and estimated glomerular filtration rate (AUC = 0.69). UAGT improved the performance of those clinical markers in diagnosing crescentic ANCA-GN (P < 0.034), suggesting a role of UAGT in identifying active crescentic ANCA-GN. In Stage II, UAGT decreased after immunotherapy and increased at the time of renal relapse during the 2-year follow-up, suggesting the usefulness of UAGT to monitor disease activity over time. CONCLUSIONS: These results suggest the potential use of UAGT for assessing disease activity and renal relapse in ANCA-GN.

Urinary angiotensinogen predicts progressive chronic kidney disease after an episode of experimental acute kidney injury.

One of the major obstacles to prevent AKI-CKD transition is the lack of effective methods to follow and predict the ongoing kidney injury after an AKI episode. In the present study, we test the utility of urinary angiotensinogen (UAGT) for dynamically evaluating renal structural changes and predicting AKI-CKD progression by using both mild and severe bilateral renal ischemia/reperfusion injury mice. UAGT returns to pre-ischemic levels 14 days after mild AKI followed by kidney architecture restoration, whereas sustained increase in UAGT accompanies by ongoing renal fibrosis after severe AKI. UAGT at day 14-42 correlates with renal fibrosis 84 days after AKI. For predicting fibrosis at day 84, the area under receiver operating characteristics curve of UAGT at day 14 is 0.81. Persistent elevation in UAGT correlates with sustained activation of intrarenal renin-angiotensin system (RAS) during AKI-CKD transition. Abrogating RAS activation post AKI markedly reduced renal fibrosis, with early RAS intervention (from 14 days after IRI) more beneficial than late intervention (from 42 days after IRI) in alleviating fibrosis. Importantly, UAGT decreases after RAS intervention, and its level at day 14-28 correlates with the extent of renal fibrosis at day 42 post RAS blockade. A pilot study conducted in patients with acute tubular necrosis finds that compared with those recovered, patients with AKI-CKD progression exhibits elevated UAGT during the 3-month follow-up after biopsy. Our study suggests that UAGT enables the dynamical monitoring of renal structural recovery after an AKI episode and may serve as an early predictor for AKI-CKD progression and treatment response.

Dapagliflozin attenuates renal fibrosis by suppressing angiotensin II/TGFß signaling in diabetic mice.

AIMS: Diabetic nephropathy (DN) complicates diabetes Mellitus and intimately relates to intrarenal renin-angiotensin system (RAS) activity. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been validated to improve renal outcomes in diabetic patients from clinical research by elusive mechanisms. This study explored the presumption that the eagerness activity of intrarenal RAS in DN generated oxidative stress to promote renal fibrosis, and the process can be interrupted by dapagliflozin. METHODS: A streptozotocin-induced DN model was established in male C57BL/6J mice. Mice were treated with dapagliflozin or losartan for 14 weeks. Biochemical data, renal fibrosis, oxidative stress, and RAS were measured. RESULTS: DN mice were characterized by overtly low body weight, high levels of blood glucose, and renal injury. Interrupting SGLT2 and RAS significantly improved renal dysfunction and pathological lesions in DN mice. Consistent with these favorable effects, dapagliflozin revoked the local RAS/oxidative stress and the succeeding transforming growth factor beta (TGFß) signaling. CONCLUSIONS: This research clarifies that intrarenal RAS activity triggers renal injury in DN, and dapagliflozin attenuates renal fibrosis by suppressing Angiotensin II/TGFß signaling. It unravels a novel insight into the role of prevention and treatment of SGLT2 inhibitors to DN.

Spatio-temporal evolution and influencing factors of high quality economic development: Case study of Guangdong-Hong Kong-Macao Greater Bay Area.

With the increase in global economic integration, high-quality economic development (HQED) has become a common goal of all countries. Based on these five development concepts, this paper uses the Gini coefficient, trend surface analysis, geographically weighted regression (GWR), the entropy weighting method, and standard deviation ellipse analysis to study the spatio-temporal pattern and driving mechanism of HQED in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA). This paper examines the spatial and temporal patterns and driving mechanisms of HQED in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) based on five development concepts. The study revealed that (1) HQED is on the rise overall, but at the same time, it highlights the uneven development of multiple dimensions, especially in terms of significant differences in innovation, openness, and sharing. (2) HQED shows a clear center-periphery structure, with Guangzhou, Shenzhen, and Hong Kong as the core high-value areas; the growth rate of HQED capacity in the internal areas is significantly greater than that in the external areas, and HQED is prominent in the cities around Guangzhou, Shenzhen, and Hong Kong. (3) Factors such as agglomeration level, human capital, foreign investment, infrastructure development, financial and environmental protection expenditures, and financial inputs, and scientific, and technological inputs have a significant positive effect on HQED, and their interactions are further strengthened. This study reveals the importance of the realization of HQED in the GBA and the promotion of the overall development of the region.

Spatial structure and network characteristics of the coupling coordination innovation ecosystems in the Guangdong-Hong Kong-Macao Greater Bay area.

In recent times, a new wave of scientific and technological advancements has significantly reshaped the global economic structure. This shift has redefined the role of regional innovation, particularly in its contribution to developing the Guangdong-Hong Kong-Macao Greater Bay area (GBA) into a renowned center for science, technology, and innovation. This study constructs a comprehensive evaluation system for the Regional Innovation Ecosystem (RIE). By applying the coupling coordination degree model and social network analysis, we have extensively analyzed the spatial structure and network attributes of the coupled and coordinated innovation ecosystem in the GBA from 2010 to 2019. Our findings reveal several key developments: (1) There has been a noticeable rightward shift in the kernel density curve, indicating an ongoing optimization of the overall coupling coordination level. Notably, the center of gravity for coupling coordination has progressively moved southeast. This shift has led to a reduction in the elliptical area each year, while the trend surface consistently shows a convex orientation toward the center. The most significant development is observed along the 'Guangdong-Shenzhen-Hong Kong-Macao Science and Technology Innovation Corridor', where the level of coupling coordination has become increasingly pronounced. (2) The spatial linkages within the GBA have been strengthening. There are significant spatial transaction costs in the regional innovation ecological network. In the context of the 2019 US-China trade war, the cities of Jiangmen and Zhaoqing experienced a notable decrease in connectivity with other cities, raising concerns about their potential marginalization. (3) Guangzhou, Shenzhen, and Hong Kong have emerged as core nodes within the network. The network exhibits a distinctive "core-edge" spatial structure, characterized by both robustness and vulnerability in various aspects.

Evolution characteristics and influencing factors of information network in Guangdong-Hong Kong-Macao Greater Bay Area.

In the context of the digital information era, the impact of "The Internet Plus," "Big Data," and other technologies on urban social development has been far beyond any preceding era, under the influence of information technology, urban agglomeration space exhibits a new layout. Based on the search engine data of eleven cities in the Guangdong-Hong Kong-Macao Greater Bay Area from 2012 to 2021, this research constructs the inter-city information network strength linkage matrix to examine the evolution characteristics of city network structure and its driving causes. The results reveal that (1) the overall information linkage strength exhibits a pattern of steadily growing the radiating effect from the leading cities of Guangdong, Shenzhen, and Hong Kong to the surrounding cities, and a closer and more balanced information linkage network is gradually built. (2) Guangzhou-Shenzhen-Hong Kong-Guangdong-Hong Kong-Macao Greater Bay Area information linkage absolute control advantage, four cities Foshan, Dongguan, Zhuhai, Macao regional hub position steadily highlighted. The entire information connection network of the urban agglomerations tends to be flat and polycentric at the same time. (3) The regional core-edge hierarchy is well established, with the four cities of Guangzhou, Dongguan, Shenzhen, and Hong Kong creating a northwest-southeast orientation. The core metropolis regions of Guangdong, Hong Kong, and Macao in the Greater Bay Area increasingly exert a radiation spreading effect to the northeast and southwest. (4) The urban economy, transportation distance, and information infrastructure have substantial effects on the information connection intensity network of urban clusters.

Response of Cd, Zn Translocation and Distribution to Organic Acids Heterogeneity in Brassica juncea L.

In order to investigate the translocation, distribution, and organic acid heterogeneity characteristics in Brassica juncea L., a pot experiment with the exogenous application of Cd and Zn was conducted to analyze the effects of Cd, Zn, and organic acid contents and heterogeneity on the translocation and distribution of Cd and Zn. The results showed that the Cd and Zn contents of B. juncea were mainly accumulated in the roots. The Cd content in the symplast sap was 127.66-146.50% higher than that in the apoplast sap, while the opposite was true for Zn. The distribution of Cd in xylem sap occupied 64.60% under 20 mg kg-1 Cd treatment, and Zn in xylem sap occupied 60.14% under 100 mg kg-1 Zn treatment. The Cd was predominantly distributed in the vacuole, but the Zn was predominantly distributed in the cell walls. In addition, oxalic and malic acids were present in high concentrations in B. juncea. In the vacuole, correlation analysis showed that the contents of Cd were negatively correlated with the contents of oxalic acid and succinic acid, and the contents of Zn were positively correlated with the contents of malic acid and acetic acid. The contents of Cd and Zn were negatively related to the contents of oxalic acid and citric acid in xylem sap. Therefore, Cd in B. juncea was mainly absorbed through the symplast pathway, and Zn was mainly absorbed through the apoplast pathway, and then Cd and Zn were distributed in the vacuole and cell walls. The Cd and Zn in B. juncea are transferred upward through the xylem and promoted by oxalic acid, malic acid, and citric acid.

Spatial-temporal differences and influencing factors of coupling coordination between urban quality and technology innovation in the Guangdong-Hong Kong-Macao Greater Bay Area.

The coordinated development of urban quality and technology innovation is an important element of China's technology innovation development strategy in the new era. Based on entropy TOPSIS, coupling coordination models, the gravity center and standard deviation ellipse method, the geographic probe, the GWR, and other methods, we explore the spatial variation and influencing factors of the coupling coordination relationship between urban quality and technology innovation in the Guangdong-Hong Kong-Macao Greater Bay Area from 2011 to 2020. It is found that: (1) the spatial distribution of the coupling coordination shows a characteristic of "high in the middle and low in the surroundings," and (2) the level of benign interaction in the central region is becoming more prominent. The center of gravity of coupling coordination moves toward the northeast, and the standard deviation ellipse shows a contraction trend away from the southwest. (3) Agglomeration capacity, human capital, cultural development, and infrastructure can significantly drive the improvement of the coupling coordination of urban quality and technology innovation, and the two-factor influence is significantly increased after the interaction. (4) The feedback effects of the coupling and coordination states of different cities on each factor have significant spatial differences and show the characteristics of hierarchical band distribution.

Neural and central mechanisms of kidney fibrosis after relief of ureteral obstruction.

Obstructive uropathy from nephrolithiasis remains a leading cause of end-stage kidney disease. Mechanisms of kidney fibrosis after relief of ureteral obstruction represent opportunities for therapeutic intervention. Here, in mouse models of ureteral obstruction, we have combined methods of virus tracing and optogenetic techniques to identify an overactive central pathway in the paraventricular nucleus (PVN)-rostral ventrolateral medulla (RVLM) that determines the fibrotic fate of kidney after relief of the obstruction. The overactive pathway is driven by kidney afferent nerves that activate angiotensin II signaling in RVLM-projecting PVN neurons to drive sympathetic discharge back to the kidney. This causes the kidney to undergo fibrosis with loss of function. Blockade of sympathetic traffic or deletion of AT1a in PVN preserves the structure of the post-obstructed kidney. Human post-obstructed kidneys also demonstrate evidence of increased sympathetic nerve activity associated with a fibrotic outcome. Manipulating these neural elements is a potential treatment strategy.

A kidney-brain neural circuit drives progressive kidney damage and heart failure.

Chronic kidney disease (CKD) and heart failure (HF) are highly prevalent, aggravate each other, and account for substantial mortality. However, the mechanisms underlying cardiorenal interaction and the role of kidney afferent nerves and their precise central pathway remain limited. Here, we combined virus tracing techniques with optogenetic techniques to map a polysynaptic central pathway linking kidney afferent nerves to subfornical organ (SFO) and thereby to paraventricular nucleus (PVN) and rostral ventrolateral medulla that modulates sympathetic outflow. This kidney-brain neural circuit was overactivated in mouse models of CKD or HF and subsequently enhanced the sympathetic discharge to both the kidney and the heart in each model. Interruption of the pathway by kidney deafferentation, selective deletion of angiotensin II type 1a receptor (AT1a) in SFO, or optogenetic silence of the kidney-SFO or SFO-PVN projection decreased the sympathetic discharge and lessened structural damage and dysfunction of both kidney and heart in models of CKD and HF. Thus, kidney afferent nerves activate a kidney-brain neural circuit in CKD and HF that drives the sympathetic nervous system to accelerate disease progression in both organs. These results demonstrate the crucial role of kidney afferent nerves and their central connections in engaging cardiorenal interactions under both physiological and disease conditions. This suggests novel therapies for CKD or HF targeting this kidney-brain neural circuit.

Urinary Angiotensinogen Predicts Renal Disease Activity in Lupus Nephritis.

Aims: A noninvasive indicator of renal histological lesions and disease activity in lupus nephritis (LN) is needed for timely and targeted treatment before overt renal injury. Here, we tested the utility of urinary angiotensinogen (UAGT) to predict renal disease activity in LN. Results: A prospective, three-stage study was performed in patients with LN. In stage I, UAGT was measured in 140 newly diagnosed LN patients. UAGT significantly increased in LN patients, correlating well with kidney angiotensinogen expression and histological activity. Patients with LN class IV exhibited the highest UAGT compared with other histopathological classes of LN. For identifying LN class IV, a particularly aggressive type of LN, UAGT outperformed the conventional clinical measures and improved their performance. In stage II, UAGT was monitored in 61 subjects from stage I for up to 12 months. UAGT decreased after induction therapy and remained low in patients with LN remission during follow-up. For predicting therapy success at month 12, the area under the receiver operating characteristics curve of UAGT reduction at month 4 was 0.83, outperforming that of 24-h proteinuria. In stage III, UAGT was monitored in 12 LN patients before, during, and after the onset of renal flares. An elevation in UAGT predicted recurrence of LN, and a decline in UAGT after a renal flare heralded the remission of disease before conventional clinical measures. Innovation and Conclusion: UAGT in LN is a promising indicator for dynamic surveillance of renal disease activity and prediction of renal flares. Antioxid. Redox Signal. 31, 1289-1301.

A renal-cerebral-peripheral sympathetic reflex mediates insulin resistance in chronic kidney disease.

BACKGROUND: Insulin resistance (IR) complicates chronic kidney disease (CKD). We tested the hypothesis that CKD activates a broad reflex response from the kidneys and the white adipose tissue to impair peripheral glucose uptake and investigated the role of salt intake in this process. METHODS: 5/6-nephrectomized rats were administered normal- or high-salt for 3 weeks. Conclusions were tested in 100 non-diabetic patients with stage 3-5 CKD. FINDINGS: High-salt in 5/6-nephrectomized rats decreased insulin-stimulated 2-deoxyglucose uptake >25% via a sympathetic nervous system (SNS) reflex that linked the IR to reactive oxygen species (ROS) and the renin-angiotensin system (RAS) in brain and peripheral tissues. Salt-loading in CKD enhanced inflammation in adipose tissue and skeletal muscle, and enhanced the impairment of insulin signaling and Glut4 trafficking. Denervation of the kidneys or adipose tissue or deafferentation of adipose tissue improved IR >40%. In patients with non-diabetic CKD, IR was positively correlated with salt intake after controlling for cofounders (r = 0.334, P = 0.001) and was linked to activation of the RAS/SNS and to impaired glucose uptake in adipose tissue and skeletal muscle, all of which depended on salt intake. INTERPRETATION: CKD engages a renal/adipose-cerebral-peripheral sympathetic reflex that activates the RAS/ROS axes to promote IR via local inflammation and impaired Glut4 trafficking that are enhanced by high-salt intake. The findings point to a role for blockade of RAS or α-and-ß-adrenergic receptors to reduce IR in patients with CKD. FUND: National Natural Science Foundation of China.