Mesangial cell-derived tenascin-C contributes to mesangial cell proliferation and matrix protein production in IgA nephropathy.

AIM: Tenascin-C (TNC), a non-structural extracellular matrix glycoprotein, is transiently expressed during development or after injury, playing an important role in injury and repair process. The potential role of TNC in the pathogenesis of IgA nephropathy (IgAN) remains to be clarified. METHODS: Immunohistochemistry staining for TNC was conducted on paraffin-embedded slices from renal biopsies of 107 IgAN patients, and correlation analysis was made between mesangial TNC expression and clinic-pathological parameters. In situ hybridization for TNC mRNA was further performed to figure out the cells that express TNC within glomeruli. In vitro experiments were also carried out on mouse mesangial cells (SV40 MES13) to elucidate the effect of TNC on mesangial cells. RESULTS: TNC was expressed in the mesangial area of IgAN, as well as in fibrotic regions. Correlation analysis showed that higher mesangial TNC was associated with higher level of proteinuria, lower estimated glomerular filtration rate and more serious pathological lesions (MEST score). In situ hybridization revealed that abundant TNC mRNA expression was observed in the affected glomeruli of IgAN, but not in minimal change disease. Moreover, TNC mRNA co-localized with PDGFRß mRNA, but not with PODXL mRNA, suggesting that TNC mRNA was expressed in the mesangial cells within glomeruli in IgAN. In vitro experiments showed that exogenous TNC promoted matrix protein production and mesangial cell proliferation, which was attenuated by an epidermal growth factor receptor inhibitor. CONCLUSION: Taken together, these results suggest that mesangial cell-derived TNC contributes to mesangial matrix expansion and mesangial cell proliferation, which is a potential therapeutic target in IgAN.

Circulating α-Klotho is Related to Plasma Aldosterone and Its Follow-Up Change Predicts CKD Progression.

BACKGROUND/AIMS: We aimed to determine if soluble α-klotho level was an indicator of chronic kidney disease (CKD) progression and whether α-klotho interacted with aldosterone during the course of further renal damage. METHODS: 112 adults with stages 1-5 CKD were enrolled into our cohort study. All of the patients were followed up for 6 years (from January 2010 to December 2015). Serum soluble α-klotho and aldosterone were measured at baseline and at 1.5-years follow-up. The primary outcome was the initiation of renal replacement therapy (RRT) and the secondary outcome was the occurrence of cardio-cerebrovascular events. Long-term progression to RRT and cardio-cerebrovascular events in patients was analyzed with a risk-adjusted Cox proportional hazards regression model. Adjustment included age, gender, eGFR, mean arterial pressure, 24-h protein excretion and the change in α-klotho level from baseline at 1.5-years follow-up. RESULTS: Baseline circulating α-klotho levels were positively associated with baseline estimated glomerular filtration rate (eGFR; r = 0.224, p = 0.017), but not age, calcium, phosphate, or parathyroid hormone levels. The change in α-klotho level from baseline at 1.5-years follow-up (p = 0.002) was independently associated with renal replace treatment (RRT) initiation after adjustment for age, gender, eGFR, mean arterial pressure, and 24-h protein excretion in Cox regression analysis. Aldosterone levels were positively associated with CKD stage, and were inversely correlated with circulating α-klotho levels. CONCLUSION: The change in concentration of soluble α-klotho during the 1.5-years follow-up was an indicator of CKD progression. Renal damage associated with a reduction of α-klotho may involve the upregulation of plasma aldosterone. Future studies are needed to validate our findings, and to investigate the underlying mechanism by which α-klotho and aldosterone may cause renal damage.

"Doing what others do" does not stabilize continuous norms.

Differences in social norms are a key source of behavioral variation among human populations. It is widely assumed that a vast range of behaviors, even deleterious ones, can persist as long as they are locally common because deviants suffer coordination failures and social sanctions. Previous models have confirmed this intuition, showing that different populations may exhibit different norms even if they face similar environmental pressures or are linked by migration. Crucially, these studies have modeled norms as having a few discrete variants. Many norms, however, have a continuous range of variants. Here we present a mathematical model of the evolutionary dynamics of continuously varying norms and show that when the social payoffs of the behavioral options vary continuously the pressure to do what others do does not result in multiple stable equilibria. Instead, factors such as environmental pressure, individual preferences, moral beliefs, and cognitive attractors determine the outcome even if their effects are weak, and absent such factors populations linked by migration converge to the same norm. The results suggest that the content of norms across human societies is less arbitrary or historically constrained than previously assumed. Instead, there is greater scope for norms to evolve towards optimal individual or group-level solutions. Our findings also suggest that cooperative norms such as those that increase contributions to public goods might require evolved moral preferences, and not just social sanctions on deviants, to be stable.

Competition for priority harms the reliability of science, but reforms can help.

Incentives for priority of discovery are hypothesized to harm scientific reliability. Here, we evaluate this hypothesis by developing an evolutionary agent-based model of a competitive scientific process. We find that rewarding priority of discovery causes populations to culturally evolve towards conducting research with smaller samples. This reduces research reliability and the information value of the average study. Increased start-up costs for setting up single studies and increased payoffs for secondary results (also known as scoop protection) attenuate the negative effects of competition. Furthermore, large rewards for negative results promote the evolution of smaller sample sizes. Our results confirm the logical coherence of scoop protection reforms at several journals. Our results also imply that reforms to increase scientific efficiency, such as rapid journal turnaround times, may produce collateral damage by incentivizing lower-quality research; in contrast, reforms that increase start-up costs, such as pre-registration and registered reports, may generate incentives for higher-quality research.

α-Klotho, Plasma Asymmetric Dimethylarginine, and Kidney Disease Progression.

RATIONALE & OBJECTIVE: We aimed to explore the associated factors of endothelial injury in chronic kidney disease (CKD) and the relationship between endothelial dysfunction and CKD prognosis. STUDY DESIGN: A prospective observational cohort study. SETTING & PARTICIPANTS: 77 adults with CKD stages 1-5 were enrolled January 2010 to December 2010 and followed up until December 2015. EXPOSURE: Serum asymmetric dimethylarginine (ADMA) level at baseline, α-klotho, sodium-phosphorus synergistic transporter, and dimethylarginine-dimethylamine hydrolase expression in kidney biopsy samples. OUTCOME: Initiation of kidney replacement therapy (KRT). ANALYTICAL APPROACH: Kaplan-Meier analysis was used for evaluation of the incidence rate of KRT. All tests were 2 tailed, and statistical significance was defined as P < 0.05. RESULTS: Mean serum ADMA level of 77 patients was 64.3 ± 34.6 ng/mL. ADMA level increased with CKD stages (P = 0.06) and declining kidney function (r = -0.267; P = 0.02). The expression of α-klotho in kidney biopsy specimens also decreased. Median follow-up time was 56 (interquartile range, 50.5-62) months. Kaplan-Meier analyses showed that during a total follow-up of 6 years, the incidence of KRT initiation in the high-ADMA group was significantly higher than that in the low group (35.9% vs 13.2%; P = 0.03). ADMA level was negatively correlated with α-klotho (r = -0.233; P = 0.04) and positively correlated with phosphorus level (r = 0.243; P = 0.04). The expression of sodium-phosphorus synergistic transporter in kidney tubules, which promoted phosphorus reabsorption, and the expression of dimethylarginine-dimethylamine hydrolase isoform 1, which regulated ADMA, were decreased. Correlation analysis also showed that ADMA level decreased while age increased at baseline (r = -0.292; P = 0.01). LIMITATIONS: Small sample size with limited longer-term follow-up. CONCLUSIONS: Serum ADMA levels increased as kidney function declined, and high serum ADMA level was associated with incident kidney failure. Low tissue α-klotho and high levels of plasma phosphorus or tissue expression of type II sodium/phosphate cotransporter in the kidney are associated with higher circulating ADMA levels, suggesting that they may be involved in the pathogenesis of endothelial dysfunction in patients with CKD.

Interstitial HIF1A induces an estimated glomerular filtration rate decline through potentiating renal fibrosis in diabetic nephropathy.

AIMS: This study aimed to identify interstitial molecules that were responsible for the deterioration of the esiantimated glomerular filtration rate (eGFR) in diabetic nephropathy (DN). MATERIALS AND METHODS: Weighted gene co-expression network analysis (WGCNA) was used to link the tubulointerstitial gene expression profile of DN to eGFR values. The relationship of eGFR with each sub-domain regulator in the network was analyzed with the linear regression model. Gene sets enrichment analysis (GSEA) was applied to detect the molecular changes mostly relating to the essential regulators. KEY FINDINGS: Four co-expression modules were found strongly correlating with eGFR values. Genes from these modules were over-represented in fibrosis-related biological processes (extracellular matrix (ECM) organization and cell adhesion) and pathways (integrin signaling and ECM-receptor interaction). Of sub-domains in the gene interaction network, the expression of hypoxia-inducible factor 1A (HIF1A) was most negatively correlated with eGFR (R2 = 0.417, P = 0.026). The positive correlations between HIF1A and its target genes were found, indicating an enhanced transcriptional activity of HIF1A. We also found that HIF1A positively correlated with CCAAT enhancer binding protein delta (CEBPD) (r = 0.731, P = 0.011), an activator of HIF1A transcription. Moreover, GSEA showed that samples with high HIF1A expression were enriched with fibrosis associated signaling, like ECM-receptor interaction and cell adhesion. Intriguingly, vascular epithelial growth factor A (VEGFA) expression decreased while HIF1A increased (R2 = 0.733, P = 0.001), suggesting VEGFA loss may exacerbate hypoxia and stimulate HIF1A induction. SIGNIFICANCE: The present study suggested that interstitial HIF1A may be involved in renal interstitial fibrosis in DN.

Aldosterone induces renal fibrosis by promoting HDAC1 expression, deacetylating H3K9 and inhibiting klotho transcription.

Aldosterone has an important role in the progression of renal fibrosis. In the present study, the concentration of aldosterone and klotho (KL) in the serum of patients with chronic kidney disease (CKD) were analyzed. A negative correlation was observed between aldosterone and KL, suggesting that KL may serve a protective role in CKD. Subsequently, an aldosterone­induced CKD mouse model was established using a single nephrectomy and subcutaneous osmotic pump with aldosterone and 1% high­salt drinking water. It was demonstrated that fibronectin 1 (Fn1) expression levels were higher in high aldosterone mice, whereas KL expression levels were low. In addition, the results demonstrated that histone deacetylase 1 (HDAC1) protein expression levels were upregulated in the renal distal convoluted tubules of high aldosterone mice, whereas acetylated H3K9 (H3K9Ac) was significantly downregulated. To determine the transcriptional activation status, chromatin immunoprecipitation polymerase chain reaction (PCR) was used to validate binding of H3K9Ac to the KL gene promoter site. It was revealed that the binding product of the KL promoter could be PCR­amplified at the H3K9Ac site from wild­type and low aldosterone mice; however, amplification of the binding product was not observed in high aldosterone mice. In conclusion, aldosterone significantly inhibited H3K9 acetylation by upregulating HDAC1 protein expression levels in the renal distal convoluted tubule cells, resulting in its inability to bind to the KL promoter, loss of transcription of the KL gene and increased expression of the renal fibrosis gene, Fn1.

Abnormal glucose metabolism and galactose-deficient immunoglobulin A1 (IgA1) synthesis: a possible mechanism of IgA nephropathy.

BACKGROUND/AIMS: It is widely accepted that a possible etiopathogenic factor associated with IgA nephropathy is the glycosylation of IgA1 molecule O-glycans. The present study aimed to determine if galactose-deficient IgA1 is related to glucose metabolism. METHODS: IgA nephropathy was identified from the renal biopsies of 108 adult patients enrolled in our study with 60 healthy controls. The concentration of serum lactose, galactose, and lactase was measured. The relationship between glucose metabolism, proteinuria, and renal pathological changes was studied. RESULTS: The circulating lactose level was higher in IgAN patients compared to that in the healthy controls [143.9 (93.9-225.6) vs. 77.9 (54.9 - 209.6); p < 0.001]. The circulating lactase level was lower in IgAN patients than that in the healthy controls (229.9 ± 57.56 vs. 270.0 ± 69.30; p < 0.001). Serum galactose level of IgAN patients was lower than that of healthy controls but without significant differences. Lactose levels showed a significant positive correlation with 24-h proteinuria (r = 0.222; p = 0.021). CONCLUSION: The differences in lactose and lactase from the IgAN patients and healthy controls may be an indicator of the possible pathogenesis of IgAN. The level of serum lactose was correlated with the level of 24-h urinary protein during the same period, suggesting that it plays a role in IgA kidney disease progression. Future studies are required to validate our findings during the follow-up and investigate the underlying mechanisms.

Modulation of aldosterone levels by aldosterone synthase promoter polymorphism and association with eGFR decline in patients with chronic kidney disease.

To determine whether -344T/C CYP11B2 promoter polymorphism affects serum aldosterone levels and whether this polymorphism is an indicator of eGFR decline in patients with chronic kidney disease. -344 C/T CYP11B2 gene polymorphism analysis was performed in 96 adults with stages 1-5 CKD by using polymerase chain reaction. Serum aldosterone levels were measured at baseline and at 1.5-year follow-up. The primary outcome was the annual eGFR decline and the secondary outcome was the occurrence of cardio-cerebrovascular events. The genotype distribution of -344T/C SNP in the patients with CKD was: CC (9.4%), CT (53.1%), and TT (37.5%), nearly similar to the healthy non-CKD individuals as reported. Mean aldosterone levels were highest in the TT group and lowest in CC group (p = 0.036). Serum aldosterone level also showed a negative correlation with baseline eGFR in patients with eGFR >60 mL/min (r = -0.403, p < 0.001). The mean annual eGFR decline ratio was highest in the TT group and lowest in the CC group (p = 0.011). The incidence of cardio-cerebrovascular accidents was significantly higher in the TT group than in the CC and CT groups (p = 0.033). -344T/C promoter polymorphism of CYP11B2 modulated aldosterone levels in patients with all stages of CKD and was predictive of annual eGFR decline in CKD stages 3-4. In addition, the -344 T allele appeared to be an independent predictor of cardio-cerebrovascular events.