m6A RNA methylation drives kidney fibrosis by upregulating ß-catenin signaling.

N6-methyladenosine (m6A) methylation plays a crucial role in various biological processes and the pathogenesis of human diseases. However, its role and mechanism in kidney fibrosis remain elusive. In this study, we show that the overall level of m6A methylated RNA was upregulated and the m6A methyltransferase METTL3 was induced in kidney tubular epithelial cells in mouse models and human kidney biopsies of chronic kidney disease (CKD). Proximal tubule-specific knockout of METTL3 in mice protected kidneys against developing fibrotic lesions after injury. Conversely, overexpression of METTL3 aggravated kidney fibrosis in vivo. Through bioinformatics analysis and experimental validation, we identified ß-catenin mRNA as a major target of METTL3-mediated m6A modification, which could be recognized by a specific m6A reader, the insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3). METTL3 stabilized ß-catenin mRNA, increased ß-catenin protein and induced its downstream profibrotic genes, whereas either knockdown of IGF2BP3 or inhibiting ß-catenin signaling abolished its effects. Collectively, these results indicate that METTL3 promotes kidney fibrosis by stimulating the m6A modification of ß-catenin mRNA, leading to its stabilization and its downstream profibrotic genes expression. Our findings suggest that targeting METTL3/IGF2BP3/ß-catenin pathway may be a novel strategy for the treatment of fibrotic CKD.

Klotho-derived peptide 1 inhibits cellular senescence in the fibrotic kidney by restoring Klotho expression via posttranscriptional regulation.

Background: Klotho deficiency is a common feature of premature aging and chronic kidney disease (CKD). As such, restoring Klotho expression could be a logic strategy for protecting against various nephropathies. In this study, we demonstrate that KP1, a Klotho-derived peptide, inhibits cellular senescence by restoring endogenous Klotho expression. Methods: The effects of KP1 on cellular senescence and Klotho expression were assessed in mouse models of CKD. RNA-sequencing was employed to identify the microRNA involved in regulating Klotho by KP1. Gain- or loss-of-function approaches were used to assess the role of miR-223-3p and IncRNA-TUG1 in regulating Klotho and cellular senescence. Results: KP1 inhibited senescence markers p21, p16 and γ-H2AX in tubular epithelial cells of diseased kidneys, which was associated with its restoration of Klotho expression at the posttranscriptional level. Profiling of kidney microRNAs by RNA sequencing identified miR-223-3p that bound to Klotho mRNA and inhibited its protein expression. Overexpression of miR-223-3p inhibited Klotho and induced p21, p16 and γ-H2AX, which were negated by KP1. Conversely, inhibition of miR-223-3p restored Klotho expression, inhibited cellular senescence. Furthermore, miR-223-3p interacted with lncRNA-TUG1 and inhibited its expression. Knockdown of lncRNA-TUG1 increased miR-223-3p, aggravated Klotho loss and worsened cellular senescence, whereas KP1 mitigated all these changes. Conclusion: These studies demonstrate that KP1 inhibits cellular senescence and induces Klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1. By restoring endogenous Klotho, KP1 elicits a broad spectrum of protective actions and could serve as a promising therapeutic agent for fibrotic kidney disorders.

Incidence, risk factors and outcome of postoperative acute kidney injury in China.

BACKGROUND: Postoperative acute kidney injury (AKI) is a common condition after surgery, however, the available data about nationwide epidemiology of postoperative AKI in China from large and high-quality studies are limited. This study aimed to determine the incidence, risk factors and outcomes of postoperative AKI among patients undergoing surgery in China. METHODS: This was a large, multicentre, retrospective study performed in 16 tertiary medical centres in China. Adult patients (≥18 years of age) who underwent surgical procedures from 1 January 2013 to 31 December 2019 were included. Postoperative AKI was defined by the Kidney Disease: Improving Global Outcomes creatinine criteria. The associations of AKI and in-hospital outcomes were investigated using logistic regression models adjusted for potential confounders. RESULTS: Among 520 707 patients included in our study, 25 830 (5.0%) patients developed postoperative AKI. The incidence of postoperative AKI varied by surgery type, which was highest in cardiac (34.6%), urologic (8.7%) and general (4.2%) surgeries. A total of 89.2% of postoperative AKI cases were detected in the first 2 postoperative days. However, only 584 (2.3%) patients with postoperative AKI were diagnosed with AKI on discharge. Risk factors for postoperative AKI included older age, male sex, lower baseline kidney function, pre-surgery hospital stay ≤3 days or >7 days, hypertension, diabetes mellitus and use of proton pump inhibitors or diuretics. The risk of in-hospital death increased with the stage of AKI. In addition, patients with postoperative AKI had longer lengths of hospital stay (12 versus 19 days) and were more likely to require intensive care unit care (13.1% versus 45.0%) and renal replacement therapy (0.4% versus 7.7%). CONCLUSIONS: Postoperative AKI was common across surgery type in China, particularly for patients undergoing cardiac surgery. Implementation and evaluation of an alarm system is important for the battle against postoperative AKI.

The influencing factors of the erythropoietin resistance index and its association with all-cause mortality in maintenance hemodialysis patients.

Anemia is a common complication of chronic kidney disease with major option treatment of erythropoiesis-stimulating agents (ESAs). This study aimed to investigate the influencing factors of erythropoietin resistance index (ERI) and its association with mortality in maintenance hemodialysis (MHD) patients. Patients enrolled from China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5 were included. ERI was calculated as follows: ESA (IU/week)/weight (kg, post-dialysis)/hemoglobin level (g/dL). The Cox regression model was used to analyze the influencing factors on survival outcomes. Stepwise multivariate logistic regression was used to identify the related risk factors, and subgroup analyses were performed. A total of 1270 MHD subjects (687 males and 583 females) were included, with an average age of 60 (49.0, 71.0) years. All subjects were divided into two groups by the median ERI of 14.03. Multivariate logistic regression showed that dialysis vintage (OR 0.957, 95% CI: 0.929-0.986), white blood cells (OR 0.900, 95% CI: 0.844-0.960), high flux dialyzer use (OR 0.866, 95% CI: 0.755-0.993), body mass index (OR 0.860, 95% CI: 0.828-0.892), males (OR 0.708, 95% CI: 0.625-0.801), and albumin (OR 0.512, 95% CI: 0.389-0.673) had a negative association with high ERI baseline (all p < 0.05). There were 176 (13.9%) deaths in total including 89 cardiac/vascular deaths during follow-up. Cox regression analysis showed that ERI was positively associated with all-cause mortality, especially in some subgroups. ERI was associated with increased all-cause mortality in MHD patients, indicating the possibility of death prediction by ERI. Patients with high ERI warrant more attention.

Inflammatory Bowel Disease With Chronic Kidney Disease and Acute Kidney Injury.

INTRODUCTION: It remains unclear whether inflammatory bowel disease is associated with long-term risk of chronic kidney disease (CKD) and acute kidney injury (AKI) in the general population. METHODS: A total of 417,302 participants, including 2,940 patients with ulcerative colitis and 1,261 patients with Crohn's disease, without previous CKD and AKI at baseline (2006-2010) from the UK Biobank were included. The study outcomes included incident CKD and AKI, ascertained by self-report data and data linkage with primary care, hospital admissions, and death registry records. Analysis was conducted in 2022. RESULTS: During a median follow-up of 12.5 years, 13,564 and 14,331 participants developed CKD and AKI, respectively. Compared with the hazard ratio for non-inflammatory bowel diseases, the hazard ratios for CKD and AKI related to inflammatory bowel diseases were 1.57 (95% CI=1.37, 1.79) and 1.96 (95% CI=1.74, 2.20) after adjustments for age, sex, and race and were 1.32 (95% CI=1.15, 1.51) and 1.70 (95% CI=1.51, 1.91) after further adjustments for biological, behavioral, and socioeconomic factors in addition to mental health and self-rated health. Similar results were found for patients with Crohn's disease (adjusted hazard ratio=1.38 (95% CI=1.09, 1.75) for CKD and 1.62 [95% CI=1.30, 2.02] for AKI) and those with ulcerative colitis (adjusted hazard ratio=1.29 (95% CI=1.09, 1.51) for CKD and 1.71 [95% CI=1.49, 1.97] for AKI) in the fully adjusted models. Genetic risks of kidney diseases did not significantly affect the association of inflammatory bowel disease with incident CKD and AKI (both p-interactions>0.05). The association between inflammatory bowel disease and the risk of incident CKD (p-interaction=0.010) and AKI (p-interaction<0.001) were stronger in younger participants than in older participants. CONCLUSIONS: Inflammatory bowel disease was associated with higher risks for CKD and AKI, independent of genetic risks of kidney diseases.

Pentraxin 3 plays a key role in tubular cell senescence and renal fibrosis through inducing ß-catenin signaling.

Renal fibrosis is the common pathological feature of various chronic kidney diseases (CKD). Tubular cell senescence plays a key role in the progression of renal fibrosis. However, the underlying mechanisms are still in mystery. In this study, we identified, Pentraxin 3 (PTX3), belonging to the Pentraxin family, is a new fibrogenic factor. PTX3 was increased in various CKD models. PTX3 was primarily localized in tubular epithelial cells and upregulated, accompanied by mitochondrial dysfunction and cellular senescence. Overexpression of PTX3 aggravated mitochondrial damage and accelerated cell senescence in tubular cells, leading to more severe fibrogenesis in kidneys. However, knockout of PTX3 significantly preserved mitochondrial homeostasis, and blocked cellular senescence in primary cultured tubular cells. Furthermore, KYA1797K, a destabilizer of ß-catenin, greatly inhibited PTX3-induced mitochondrial dysfunction, tubular cell senescence, and renal fibrosis. Overexpression of PTX3 triggered nuclear translocation of ß-catenin, an activating form of ß-catenin. PTX3-induced mitochondrial dysfunction and tubular cell senescence were also significantly inhibited by knockdown of p16INK4A, a senescence-related protein. In a clinical cohort, we found PTX3 was increased in urine and serum in patients with CKD. Urinary PTX3 negatively correlated with eGFR. PTX3 also increased gradually following the severity of diseases, triggering the fibrogenesis. Taken together, our results provide strong evidences that PTX3 is a new fibrogenic factor in the development of renal fibrosis through ß-catenin-induced mitochondrial dysfunction and cell senescence. This study further suggests PTX3 is a new diagnostic factor to renal fibrosis and provides a new therapeutic target against renal fibrosis.

Macrophage promotes fibroblast activation and kidney fibrosis by assembling a vitronectin-enriched microenvironment.

Background: Renal infiltration of inflammatory cells including macrophages is a crucial event in kidney fibrogenesis. However, how macrophage regulates fibroblast activation in the fibrotic kidney remains elusive. In this study, we show that macrophages promoted fibroblast activation by assembling a vitronectin (Vtn)-enriched, extracellular microenvironment. Methods: We prepared decellularized kidney tissue scaffold (KTS) from normal and fibrotic kidney after unilateral ischemia-reperfusion injury (UIRI) and carried out an unbiased quantitative proteomics analysis. NRK-49F cells were seeded on macrophage-derived extracellular matrix (ECM) scaffold. Genetic Vtn knockout (Vtn-/-) mice and chronic kidney disease (CKD) model with overexpression of Vtn were used to corroborate a role of Vtn/integrin αvß5/Src in kidney fibrosis. Results: Vtn was identified as one of the most upregulated proteins in the decellularized kidney tissue scaffold from fibrotic kidney by mass spectrometry. Furthermore, Vtn was upregulated in the kidney of mouse models of CKD and primarily expressed and secreted by activated macrophages. Urinary Vtn levels were elevated in CKD patients and inversely correlated with kidney function. Genetic ablation or knockdown of Vtn protected mice from developing kidney fibrosis after injury. Conversely, overexpression of Vtn exacerbated renal fibrotic lesions and aggravated renal insufficiency. We found that macrophage-derived, Vtn-enriched extracellular matrix scaffold promoted fibroblast activation and proliferation. In vitro, Vtn triggered fibroblast activation by stimulating integrin αvß5 and Src kinase signaling. Either blockade of αvß5 with neutralizing antibody or pharmacological inhibition of Src by Saracatinib abolished Vtn-induced fibroblast activation. Moreover, Saracatinib dose-dependently ameliorated Vtn-induced kidney fibrosis in vivo. These results demonstrate that macrophage induces fibroblast activation by assembling a Vtn-enriched extracellular microenvironment, which triggers integrin αvß5 and Src kinase signaling. Conclusion: Our findings uncover a novel mechanism by which macrophages contribute to kidney fibrosis via assembling a Vtn-enriched extracellular niche and suggest that disrupting fibrogenic microenvironment could be a therapeutic strategy for fibrotic CKD.

Generation and characterization of an inducible renal proximal tubule-specific CreERT2 mouse.

Protein reabsorption in renal proximal tubules is essential for maintaining nutrient homeostasis. Renal proximal tubule-specific gene knockout is a powerful method to assess the function of genes involved in renal proximal tubule protein reabsorption. However, the lack of inducible renal proximal tubule-specific Cre recombinase-expressing mouse strains hinders the study of gene function in renal proximal tubules. To facilitate the functional study of genes in renal proximal tubules, we developed an AMN CreERT2 knock-in mouse strain expressing a Cre recombinase-estrogen receptor fusion protein under the control of the promoter of the amnionless (AMN) gene, a protein reabsorption receptor in renal proximal tubules. AMN CreERT2 knock-in mice were generated using the CRISPR/Cas9 strategy, and the tissue specificity of Cre activity was investigated using the Cre/loxP reporter system. We showed that the expression pattern of CreERT2-mEGFP in AMN CreERT2 mice was consistent with that of the endogenous AMN gene. Furthermore, we showed that the Cre activity in AMN CreERT2 knock-in mice was only detected in renal proximal tubules with high tamoxifen induction efficiency. As a proof-of-principle study, we demonstrated that renal proximal tubule-specific knockout of Exoc4 using AMNCreERT2 led to albumin accumulation in renal proximal tubular epithelial cells. The AMN CreERT2 mouse is a powerful tool for conditional gene knockout in renal proximal tubules and should offer useful insight into the physiological function of genes expressed in renal proximal tubules.

Detecting Neonatal AKI by Serum Cystatin C.

SIGNIFICANCE STATEMENT: Serum creatinine is not a sensitive biomarker for neonatal AKI because it is confounded by maternal creatinine level, gestational age, and neonatal muscle mass. In this multicenter cohort study of 52,333 hospitalized Chinese neonates, the authors proposed serum cystatin C-related criteria (CyNA) for neonatal AKI. They found that cystatin C (Cys-C) is a robust and sensitive biomarker for identifying AKI in neonates who are at an elevated risk of in-hospital mortality and that CyNA detects 6.5 times as many cases as the modified Kidney Disease Improving Global Outcomes creatinine criteria. They also show that AKI can be detected using a single test of Cys-C. These findings suggest that CyNA shows promise as a powerful and easily applicable tool for detecting AKI in neonates. BACKGROUND: Serum creatinine is not a sensitive biomarker for AKI in neonates. A better biomarker-based criterion for neonatal AKI is needed. METHODS: In this large multicenter cohort study, we estimated the upper normal limit (UNL) and reference change value (RCV) of serum cystatin C (Cys-C) in neonates and proposed cystatin C-based criteria (CyNA) for detecting neonatal AKI using these values as the cutoffs. We assessed the association of CyNA-detected AKI with the risk of in-hospital death and compared CyNA performance versus performance of modified Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria. RESULTS: In this study of 52,333 hospitalized neonates in China, Cys-C level did not vary with gestational age and birth weight and remained relatively stable during the neonatal period. CyNA criteria define AKI by a serum Cys-C of ≥2.2 mg/L (UNL) or an increase in Cys-C of ≥25% (RCV) during the neonatal period. Among 45,839 neonates with measurements of both Cys-C and creatinine, 4513 (9.8%) had AKI detected by CyNA only, 373 (0.8%) by KDIGO only, and 381 (0.8%) by both criteria. Compared with neonates without AKI by both criteria, neonates with AKI detected by CyNA alone had an increased risk of in-hospital mortality (hazard ratio [HR], 2.86; 95% confidence interval [95% CI], 2.02 to 4.04). Neonates with AKI detected by both criteria had an even higher risk of in-hospital mortality (HR, 4.86; 95% CI, 2.84 to 8.29). CONCLUSIONS: Serum Cys-C is a robust and sensitive biomarker for detecting neonatal AKI. Compared with modified KDIGO creatinine criteria, CyNA is 6.5 times more sensitive in identifying neonates at elevated risk of in-hospital mortality.

Prevalence of Chronic Kidney Disease in China: Results From the Sixth China Chronic Disease and Risk Factor Surveillance.

Importance: To our knowledge, there has been no update on the prevalence of chronic kidney disease (CKD) in China since 2012. Objective: To provide periodic nationwide data on the prevalence of CKD and the associated behavioral and metabolic risk factors in China. Design, Setting, and Participants: This nationally representative cross-sectional study included data from 176 874 adults from all 31 provincial-level administrative divisions in mainland China, as reported in the sixth China Chronic Disease and Risk Factor Surveillance conducted from August 2018 to June 2019. Data analysis was performed in 2021 to 2022. Exposures: Serum creatinine, urinal creatinine, and urine albumin were measured for all participants. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine using the CKD-EPI equation. Main Outcomes and Measures: The primary outcome was weighted prevalence of CKD in the overall population and different strata, defined as presence of impaired kidney function (eGFR of <60 mL/min/1.73m2) or albuminuria (urine albumin-to-creatinine ratio of ≥30 mg/g). Secondary outcomes were awareness of CKD and control of comorbidities. Logistic regression was used to examine the association of sociodemographic characteristics, behavioral and dietary habits, physical activity, and comorbidities with CKD. Results: A total of 184 876 participants contributed data to this study, and of the 176 874 adults 18 years and older with measurements of eGFR and urine albumin-to-creatinine ratio in 2018 to 2019, the mean age was 43.8 years and the weighted proportion of women was 44.6%. The estimated prevalence of CKD, impaired kidney function, and albuminuria were 8.2%, 2.2%, and 6.7%, respectively. A higher prevalence of CKD was observed in the subgroups characterized by older age, female gender, non-Han ethnicity, residency of rural or north and central parts of China, receiving less education or lower income, former smoking, no alcohol drinking, lacking physical activity, and presence of risk factors such as obesity, hypertension, diabetes, dyslipidemia, and self-reported cardiovascular disease. Among the adults with CKD, 73.3%, 25.0%, and 1.8% were at stage 1 to 2, 3, and 4 to 5, respectively, and the awareness of CKD was 10.0%. Conclusions and Relevance: This cross-sectional study found a weighted estimated of 82 million adults with CKD in China in 2018 to 2019. The prevalence appears to have decreased by 30% in the past decade. Better environmental protection, integration of CKD into the national public health surveillance program, and control of common CKD comorbidities appear to be associated with reducing the disease burden of CKD.

Associations between visceral adiposity index and incident nephropathy outcomes in diabetic patients: Insights from the ACCORD trial.

AIMS: Visceral adiposity index (VAI) was a reliable marker for visceral adiposity accumulation and dysfunction. The association between VAI and nephropathy outcomes remains uncertain in patients with type 2 diabetes (T2DM). We aimed to evaluate the longitudinal relationships between VAI and incident nephropathy outcomes in T2DM patients. MATERIALS AND METHODS: Ten thousand one hundred and thirty two participants with T2DM from the ACCORD trial were included in the present study. Cumulative average VAI based on VAI measurements at baseline and follow-up was used to represent long-term VAI status. The primary outcome was the incident composite nephropathy outcome defined as: (1) serum creatinine doubling or >20 ml/min decrease in eGFR; or (2) development of macro-albuminuria; or (3) renal failure or end stage kidney disease (dialysis) or serum creatinine >3.3 mg/dl. RESULTS: During 26,168 person-years follow-up duration, 6094 (60.1%) participants developed the incident composite nephropathy outcome. When assessing cumulative average VAI as quartiles, compared with those in the 1-2 quartiles (<2.6), a significantly higher risk of incident composite nephropathy outcomes was observed among participants in the 3-4 quartiles (≥2.6, adjusted HR: 1.09, 95% CI: 1.01, 1.18). Moreover, the positive association was consistent in participants with or without single abnormal VAI components, including general obesity, abdominal obesity, elevated triglycerides, and low high-density lipoprotein cholesterol, or with different numbers of abnormal VAI components. Additionally, the positive association was stronger in participants with cumulative average systolic blood pressure <130 mmHg (vs. ≥130 mmHg; p-interaction < 0.001). CONCLUSIONS: In T2DM patients, higher cumulative average VAI was associated with a higher risk of incident composite nephropathy outcomes. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, identifier: NCT00000620.

Use of Histologic Parameters to Predict Glomerular Disease Progression: Findings From the China Kidney Biopsy Cohort Study.

RATIONALE & OBJECTIVE: Challenges in achieving valid risk prediction and stratification impede treatment decisions and clinical research design for patients with glomerular diseases. This study evaluated whether chronic histologic changes, when complementing other clinical data, improved the prediction of disease outcomes across a diverse group of glomerular diseases. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 4,982 patients with biopsy-proven glomerular disease who underwent native biopsy at 8 tertiary care hospitals across China in 2004-2020. NEW PREDICTORS & ESTABLISHED PREDICTORS: Chronicity scores depicted as 4 categories of histological chronic change, as well as baseline clinical and demographic variables. OUTCOME: Progression of glomerular disease defined as a composite of kidney failure or a ≥40% decrease in estimated glomerular filtration rate from the measurement at the time of biopsy. ANALYTICAL APPROACH: Multivariable Cox proportional hazard models. The performance of predictive models was evaluated by C statistic, time-dependent area under the receiver operating characteristic curve (AUROC), net reclassification index, integrated discrimination index, and calibration plots. RESULTS: The derivation and validation cohorts included 3,488 and 1,494 patients, respectively. During a median of 31 months of follow-up, a total of 444 (8.9%) patients had disease progression in the 2 cohorts. For prediction of the 2-year risk of disease progression, the AUROC of the model combining chronicity score and the Kidney Failure Risk Equation (KFRE) in the validation cohort was 0.76 (95% CI, 0.65-0.87); in comparison with the KFRE model (AUROC, 0.68 [95% CI, 0.56-0.79]), the combined model was significantly better (P = 0.04). The combined model also had a better fit, with a lower Akaike information criterion and a significant improvement in reclassification as assessed by the integrated discrimination improvements and net reclassification improvements. Similar improvements in predictive performance were observed in subgroup and sensitivity analyses. LIMITATIONS: Selection bias, relatively short follow-up, lack of external validation. CONCLUSIONS: Adding histologic chronicity scores to the KFRE model improved the prediction of kidney disease progression at the time of kidney biopsy in patients with glomerular diseases. PLAIN-LANGUAGE SUMMARY: Risk prediction and stratification remain big challenges for treatment decisions and clinical research design for patients with glomerular diseases. The extent of chronic changes is an important component of kidney biopsy evaluations in glomerular disease. In this large multicenter cohort including 4,982 Chinese adults undergoing native kidney biopsy, we evaluated whether histologic chronicity scores, when added to clinical data, could improve the prediction of disease prognosis for a diverse set of glomerular diseases. We observed that adding histologic chronicity scores to the kidney failure risk equation improved the prediction of kidney disease progression at the time of kidney biopsy in patients with glomerular diseases.

Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair.

The mechanisms underlying fibrogenic responses after injury are not well understood. Epithelial cell cycle arrest in G2/M after injury is a key checkpoint for determining wound-healing leading to either normal cell proliferation or fibrosis. Here, we identify a kidney- and liver-enriched circular RNA, circBNC2, which is abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insult. Loss of circBNC2 is at least partially mediated by upregulation of DHX9. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrate that circBNC2 acts as a negative regulator of cell G2/M arrest by encoding a protein that promotes formation of CDK1/cyclin B1 complexes. Restoring circBNC2 in experimentally-induced male mouse models of fibrotic kidney and liver, decreases G2/M arrested cell numbers with secretion of fibrotic factors, thereby mitigating extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increased G2/M arrest of epithelial cells are recapitulated in human ischemic reperfusion injury (IRI)-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that restoring circBNC2 might represent a potential strategy for therapeutic intervention in epithelial organ fibrosis.

A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells.

Background: Liver kinase B1 (LKB1) is the key regulator of energy metabolism and cell homeostasis. LKB1 dysfunction plays a key role in renal fibrosis. However, LKB1 activators are scarce in commercial nowadays. This study aims to discover a new drug molecule, piericidin analogue S14 (PA-S14), preventing renal fibrosis as a novel activator to LKB1. Methods: Our group isolated PA-S14 from the broth culture of a marine-derived Streptomyces strain and identified its binding site. We adopted various CKD models or AKI-CKD model (5/6 nephrectomy, UUO, UIRI and adriamycin nephropathy models). TGF-ß-stimulated renal tubular cell culture was also tested. Results: We identified that PA-S14 binds with residue D176 in the kinase domain of LKB1, and then induces the activation of LKB1 through its phosphorylation and complex formation with MO25 and STRAD. As a result, PA-S14 promotes AMPK activation, triggers autophagosome maturation, and increases autophagic flux. PA-S14 inhibited tubular cell senescence and retarded fibrogenesis through activation of LKB1/AMPK signaling. Transcriptomics sequencing and mutation analysis further demonstrated our results. Conclusion: PA-S14 is a novel leading compound of LKB1 activator. PA-S14 is a therapeutic potential to renal fibrosis through LKB1/AMPK-mediated autophagy and mitochondrial homeostasis pathways.

Retraction Notice to: lncRNA lnc-TSI Inhibits Metastasis of Clear Cell Renal Cell Carcinoma by Suppressing TGF-ß-Induced Epithelial-Mesenchymal Transition.

[This retracts the article DOI: 10.1016/j.omtn.2020.08.003.].

Organic Anion Transporter Gene Variants Associated With Plasma Exposure and Long-Term Response to Atrasentan in Patients With Diabetic Kidney Disease.

Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25-75 mL/min/1.73 m2 , and a urine albumin-to-creatinine ratio of 300-5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma-concentration time curve from zero to infinity (AUC0-inf ) 41.3 ng·h/mL) or slow (atrasentan AUC0-inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45-0.81) and 1.35 (95% CI: 0.84-2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95-4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37-12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.

Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/ß-catenin signaling.

Diabetic kidney disease (DKD) is one of the most common and devastating complications of diabetic mellitus, and its prevalence is rising worldwide. Klotho, an anti-aging protein, is kidney protective in DKD. However, its large size, prohibitive cost and structural complexity hamper its potential utility in clinics. Here we report that Klotho-derived peptide 6 (KP6) mimics Klotho function and ameliorates DKD. In either an accelerated model of DKD induced by streptozotocin and advanced oxidation protein products in unilateral nephrectomized mice or db/db mice genetically prone to diabetes, chronic infusion of KP6 reversed established proteinuria, attenuated glomerular hypertrophy, mitigated podocyte damage, and ameliorated glomerulosclerosis and interstitial fibrotic lesions, but did not affect serum phosphorus and calcium levels. KP6 inhibited ß-catenin activation in vivo and blocked the expression of its downstream target genes in glomerular podocytes and tubular epithelial cells. In vitro, KP6 prevented podocyte injury and inhibited ß-catenin activation induced by high glucose without affecting Wnt expression. Co-immunoprecipitation revealed that KP6 bound to Wnt ligands and disrupted the engagement of Wnts with low density lipoprotein receptor-related protein 6, thereby interrupting Wnt/ß-catenin signaling. Mutated KP6 with a scrambled amino acid sequence failed to bind Wnts and did not alleviate DKD in db/db mice. Thus, our studies identified KP6 as a novel Klotho-derived peptide that ameliorated DKD by blocking Wnt/ß-catenin. Hence, our findings also suggest a new therapeutic strategy for the treatment of patients with DKD.

Bidirectional relations between depression symptoms and chronic kidney disease.

BACKGROUND: Depression and chronic kidney disease (CKD) often coexist. However, both the relations of depression with CKD development and CKD with depression risk were still elusive. We aimed to investigate the bidirectional relations between renal function and depression in a cohort of young and middle-aged adults. METHODS: Using data from the Coronary Artery Risk Development in Young Adults study, the analysis of depressive symptoms and incident CKD (analysis 1) was performed in 3,731 participants without CKD, and the analysis of renal function and incident depression (analysis 2) was performed in 2,994 participants without depression. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (-CES-D), and depression was defined as CES-D scores ≥16 or self-reported history of depression or antidepressant medication use. CKD was defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 or urinary albumin to creatinine ratio ≥30 mg/g. RESULTS: In analysis 1, 485 participants developed incident CKD during 61,202 person-years of follow-up, and CES-D scores (≥16 vs. <16; adjusted HR, 1.28; 95% CI, 1.04 to 1.59) were significant positive associated with incident CKD. In analysis 2, 1,029 participants developed incident depression during 42,927 person-years of follow-up, and CKD was significantly associated with a 36% increased risk of incident depression compared to non-CKD (HR, 1.36; 95% CI, 1.05 to 1.76). LIMITATIONS: Depressive symptoms were only assessed using CES-D score, which is not the gold standard for the clinical diagnosis of depression. CONCLUSIONS: This prospective cohort study monitored over 20 years indicated a bidirectional association between depression and CKD.

Association of acute kidney disease with the prognosis of ischemic stroke in the Third China National Stroke Registry.

BACKGROUND: Acute kidney disease (AKD) evolves a spectrum of acute and subacute kidney disease requiring a global strategy to address. The present study aimed to explore the impact of AKD on the prognosis of ischemic stroke. METHODS: The Third China National Stroke Registry (CNSR-III) was a nationwide registry of ischemic stroke or transient ischemic attack between August 2015 and March 2018. As a subgroup of CNSR-III, the patients who had serum creatinine (sCr) and serum cystatin C (sCysC) centrally tested on admission and at 3-month, and with 1-year follow-up data were enrolled. Modified AKD criteria were applied to identify patients with AKD during the first 3 months post stroke according to the guidelines developed by the Kidney Disease: Improving Global Outcomes in 2012. The primary clinical outcome was 1-year all-cause death, and secondary outcomes were stroke recurrence and post stroke disability. RESULTS: Five thousand sixty-five patients were recruited in the study. AKD was identified in 3.9%, 6.7%, 9.9% and 6.2% of the patients by using sCr, sCr-based estimated glomerular filtration rate (eGFRsCr), sCysC-based eGFR (eGFRsCysC), and combined sCr and sCysC-based eGFR (eGFRsCr+sCysC) criteria, respectively. AKD defined as sCr or eGFRsCr criteria significantly increased the risk of all-cause mortality (adjusted HR 2.67, 95% CI: 1.27-5.61; adjusted HR 2.19, 95% CI: 1.17-4.10) and post stroke disability (adjusted OR 1.60, 95% CI: 1.04-2.44; adjusted OR 1.51, 95% CI: 1.08-2.11). AKD diagnosed by eGFRsCysC or eGFRsCr+sCysC criteria had no significant impact on the risk of all-cause death and post stroke disability. AKD, defined by whichever criteria, was not associated with the risk of stroke recurrence in the adjusted model. CONCLUSIONS: AKD, diagnosed by sCr or eGFRsCr criteria, were independently associated with 1-year all-cause death and post stroke disability in Chinese ischemic stroke patients.

A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-ß signaling.

Loss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases. As Klotho is a large transmembrane protein, it is challenging to harness it as a therapeutic remedy. Here we report the discovery of a Klotho-derived peptide 1 (KP1) protecting kidneys by targeting TGF-ß signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-ß receptor 2 (TßR2) and disrupting the TGF-ß/TßR2 engagement. As such, KP1 blocked TGF-ß-induced activation of Smad2/3 and mitogen-activated protein kinases. In mouse models of renal fibrosis, intravenous injection of KP1 resulted in its preferential accumulation in injured kidneys. KP1 preserved kidney function, repressed TGF-ß signaling, ameliorated renal fibrosis and restored endogenous Klotho expression. Together, our findings suggest that KP1 recapitulates the anti-fibrotic action of Klotho and offers a potential remedy in the fight against fibrotic kidney diseases.