Collectin 11 has a pivotal role in host defense against kidney and bladder infection in mice.

The urinary tract is constantly exposed to microorganisms. Host defense mechanisms in protection from microbial colonization and development of urinary tract infections require better understanding to control kidney infection. Here we report that the lectin collectin 11 (CL-11), particularly kidney produced, has a pivotal role in host defense against uropathogen infection. CL-11 was found in mouse urine under normal and pathological conditions. Mice with global gene ablation of Colec11 had increased susceptibility to and severity of kidney and to an extent, bladder infection. Mice with kidney-specific Colec11 ablation exhibited a similar disease phenotype to that observed in global Colec11 deficient mice, indicating the importance of kidney produced CL-11 for protection against kidney and bladder infection. Conversely, intravesical or systemic administration of recombinant CL-11 reduced susceptibility to and severity of kidney and bladder infection. Mechanism analysis revealed that CL-11 can mediate several key innate defense mechanisms (agglutination, anti- adhesion, opsonophagocytosis), and limit local inflammatory responses to pathogens. Furthermore, CL-11-mediated innate defense mechanisms can act on clinically relevant microorganisms including multiple antibiotic resistant strains. CL-11 was detectable in eight of 24 urine samples from patients with urinary tract infections but not detectable in urine samples from ten healthy individuals. Thus, our findings demonstrate that CL-11 is a key factor of host defense mechanisms in kidney and bladder infection with therapeutic potential for human application.

First reported case of ANCA-associated vasculitis induced by oxaliplatin, capecitabine, and trastuzumab.

A 68-year-old male, who was undergoing XELOX plus trastuzumab therapy for gastric cancer, developed proteinuria, hematuria, and progressive increase in creatinine after 3 months. Subsequently, the patient also experienced hemoptysis, nasal bleeding. Chest CT examination shown pulmonary hemorrhage. The MRI of the nasopharynx ruled out nasopharyngeal cancer recurrence. The MPO and PR3 were elevated, and renal biopsy confirmed ANCA-related vasculitis, which affected the lungs, kidneys, and nasopharynx. Based on the review of the patient''s medical history and medication, it is believed that ANCA-related vasculitis was caused by XELOX plus trastuzumab chemotherapy, but it is difficult to confirm which specific drug caused it. After stopping XELOX plus trastuzumab chemotherapy, glucocorticoids and cyclophosphamide was given, the patient''s pulmonary hemorrhage and nasal bleeding stopped, and the lung lesions were absorbed. The renal function also improved. The patient later experienced pulmonary infection again, and tNGS indicated Legionella pneumophila and pulmonary tuberculosis infection. Despite anti-infection treatment, steroid dose was rapidly reduced. Ultimately, the patient gave up on treatment and eventually died.

A set of urinary peptides can predict early renal damage in primary hypertension.

OBJECTIVES: Renal diseases caused by primary hypertension (HTN) are often asymptomatic without sensitive markers for early diagnosis and prediction, easily progressing to severe and irreversible renal damage in patients with clinical manifestations. This study explored whether a set of urinary peptides could serve as a potential biomarker for early prediction of renal damage in HTN. METHODS: Urinary peptides level of healthy individuals, HTN + normoalbuminuric and HTN + albuminuria patients were compared, and 22 baseline data including sex, age, renal function, hypertensive fundus lesions were collected. Patients diagnosed with HTN, albuminuria, and normal renal function were followed up. According to the follow-up results, the cut-off value of a set of urinary peptides in predicting hypertensive renal injury was calculated and analyzed in the high-risk and low-risk groups of HTN patients for its performance in detecting early hypertensive renal injury. RESULTS: Among a sum of 319 participants, average urinary peptides level was significantly higher in patients with HTN than in normal individuals. A total of 147 HTN patients with normal albuminuria were followed up for a mean of 3.8 years. Thirty-five patients showed urinary albumin-to-creatinine ratio (uACR) at least 30 mg/g for three consecutive times. The receiver-operating characteristic (ROC) curve showed that the urinary peptides cut-off value for evaluating new-onset proteinuria in patients with HTN was 0.097. Based on this cut-off value, 39 and 108 patients were included in the high-risk and low-risk groups, respectively. Specifically, compared with patients in the low-risk group, those in the high-risk group showed significantly longer duration of HTN, higher proportions of hypertensive fundus lesions and at least 30 mg/g uACR, and higher levels of homocysteine (Hcy), cystatin C (CysC), beta-2 microglobulin (ß2-MG), and uACR. 76.9% of high-risk patients had significantly higher new-onset proteinuria than the low-risk group. Correlation analysis demonstrated a positive correlation between urinary peptides and UACR ( r  = 0.494, P  < 0.001). The incidence of new-onset albuminuria was significantly higher in the high-risk group than in the low-risk group, as shown by Cox regression analysis. The areas under the curve of urinary peptides, Hcy, ß2-MG and CysC were 0.925, 0.753, 0.796 and 0.769, respectively. CONCLUSION: A set of urinary peptides is a predictor of new-onset proteinuria in patients with HTN, therefore, it can be used for diagnosing patients with early renal injury in patients with HTN, contributing to early prevention and treatment of hypertensive nephropathy.

Decreased TAX1BP1 participates in systemic lupus erythematosus by regulating monocyte/macrophage function.

Systemic lupus erythematosus (SLE) involves disorders of innate and adaptive immune pathways. Tax1-binding protein 1 (TAX1BP1) modulates the production of antibodies in B cells and the T-cell cycle by regulating the NF-κB signaling pathway. However, the potential association of TAX1BP1 with SLE and its role in monocytes/macrophages have not been fully elucidated. In this study, we utilized whole-exome sequencing (WES) in combination with Sanger sequencing and identified 16 gene mutations, including in TAX1BP1, in an SLE family. TAX1BP1 protein expression with western blotting detection was reduced in SLE patients and correlated with disease activity negatively. Furthermore, RNA sequencing and 4D Label-Free Phosphoproteomic analysis were employed to characterize the transcriptome and phosphoproteome profiles in THP-1 and THP-1-differentiated M1 macrophages with TAX1BP1 knockdown. Silencing of TAX1BP1 in THP-1 and THP-1-differentiated M1 macrophages led to an increase in cluster of differentiation 80 (CD80) expression and differential changes in CD14 and CD16 expression, as assessed by flow cytometry. Additionally, western blot analysis showed that knockdown of TAX1BP1 led to a reduction in TRAF6 and p-p65 in THP-1-differentiated macrophages, with or without lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α stimulation. Taken together, our findings suggest that TAX1BP1 participates in SLE activity by regulating antigen presentation in monocytes and inflammatory responses in M1 macrophages.

A classifier based on 273 urinary peptides predicts early renal damage in primary hypertension.

OBJECTIVES: Renal diseases caused by primary hypertension (HTN) are often asymptomatic without sensitive markers for early diagnosis and prediction, easily progressing to severe and irreversible renal damage in patients with clinical manifestations. This study explored whether a classifier developed based on 273 urinary peptides (CKD273) could serve as a potential biomarker for early prediction of renal damage in HTN. METHODS: Urinary CKD273 level of healthy individuals, HTN + normoalbuminuric and HTN + albuminuria patients were compared, and 22 baseline data including sex, age, renal function, and hypertensive fundus lesions were collected. Patients diagnosed with HTN, albuminuria, and normal renal function were followed up. According to the follow-up results, the cut-off value of CKD273 in predicting hypertensive renal injury was calculated and analyzed in the high-risk and low-risk groups of HTN patients for its performance in detecting early hypertensive renal injury. RESULTS: Among a sum of 319 participants, average urinary CKD273 level was significantly higher in patients with HTN than in normal individuals. A total of 147 HTN patients with normal albuminuria were followed up for a mean of 3.8 years. Thirty-five patients showed urinary albumin-to-creatinine ratio (uACR) at least 30 mg/g for three consecutive times. The receiver-operating characteristic (ROC) curve showed that the urinary CKD273 cut-off value for evaluating new-onset proteinuria in patients with HTN was 0.097. Based on this cut-off value, 39 and 108 patients were included in the high-risk and low-risk groups, respectively. Specifically, compared with patients in the low-risk group, those in the high-risk group showed significantly longer duration of HTN, higher proportions of hypertensive fundus lesions and at least 30 mg/g uACR, and higher levels of homocysteine (Hcy), cystatin C (CysC), beta-2 microglobulin (ß2-MG), and uACR. 76.9% of high-risk patients had significantly higher new-onset proteinuria than the low-risk group. Correlation analysis demonstrated a positive correlation between urinary CKD273 and UACR ( r  = 0.494, P  = 0.000). The incidence of new-onset albuminuria was significantly higher in the high-risk group than in the low-risk group, as shown by Cox regression analysis. The areas under the curve of CKD273, Hcy, ß2-MG, and CysC were 0.925, 0.753, 0.796, and 0.769, respectively. CONCLUSION: Urinary CKD273 is a predictor of new-onset proteinuria in patients with HTN, therefore, it can be used for diagnosing patients with early renal injury in patients with HTN, contributing to early prevention and treatment of hypertensive nephropathy.

LncRNA 148400 Promotes the Apoptosis of Renal Tubular Epithelial Cells in Ischemic AKI by Targeting the miR-10b-3p/GRK4 Axis.

Although recent studies have reported that long non-coding RNA (lncRNA) is involved in the development of ischemic acute kidney injury (AKI), the exact function and regulatory mechanism of lncRNAs in ischemic AKI remain largely unknown. Herein, we found that ischemic injury promoted the expression of lncRNA 148400 in mouse proximal tubule-derived cell line (BUMPT) and C57BL/6J mice. Furthermore, the lncRNA148400 mediates ischemic injury-induced apoptosis of BUMPT cells. Mechanistically, lncRNA 148400 sponged miR-10b-3p to promote apoptosis via GRK4 upregulation. Finally, knockdown of lncRNA 148400 alleviated the I/R-induced deterioration of renal function, renal tubular injury, and cell apoptosis. In addition, cleaved caspase-3 is increased via targeting the miR-10b-3p/GRK4 axis. Collectively, these results showed that lncRNA 148400/miR-10b-3p/GRK4 axis mediated the development of ischemic AKI.

Protective role for C3aR in experimental chronic pyelonephritis.

Emerging evidence suggest that C3aR plays important roles in homeostasis, host defense and disease. Although it is known that C3aR is protective in several models of acute bacterial infections, the role for C3aR in chronic infection is largely unknown. Here we show that C3aR is protective in experimental chronic pyelonephritis. Global C3aR deficient (C3ar-/- ) mice had higher renal bacterial load, more pronounced renal histological lesions, increased renal apoptotic cell accumulation, tissue inflammation and extracellular matrix deposition following renal infection with uropathogenic E. coli (UPEC) strain IH11128, compared to WT control mice. Myeloid C3aR deficient (Lyz2-C3ar-/- ) mice exhibited a similar disease phenotype to global C3ar-/- mice. Pharmacological treatment with a C3aR agonist reduced disease severity in experimental chronic pyelonephritis. Furthermore, macrophages of C3ar-/- mice exhibited impaired ability to phagocytose UPEC. Our data clearly demonstrate a protective role for C3aR against experimental chronic pyelonephritis, macrophage C3aR plays a major role in the protection, and C3aR is necessary for phagocytosis of UPEC by macrophages. Our observation that C3aR agonist curtailed the pathology suggests a therapeutic potential for activation of C3aR in chronic infection.

Potential Therapeutic Strategies for Renal Fibrosis: Cordyceps and Related Products.

At present, there is no effective drug for the treatment of renal fibrosis; in particular, a safe and effective treatment for renal fibrosis should be established. Cordyceps has several medical effects, including immunoregulatory, antitumor, anti-inflammatory, and antioxidant effects, and may prevent kidney, liver, and heart diseases. Cordyceps has also been reported to be effective in the treatment of renal fibrosis. In this paper, we review the potential mechanisms of Cordyceps against renal fibrosis, focusing on the effects of Cordyceps on inflammation, oxidative stress, apoptosis, regulation of autophagy, reduction of extracellular matrix deposition, and fibroblast activation. We also discuss relevant published clinical trials and meta-analyses. Available clinical studies support the possibility that Cordyceps and related products provide benefits to patients with chronic kidney diseases as adjuvants to conventional drugs. However, the existing clinical studies are limited by low quality and significant heterogeneity. The use of Cordyceps and related products may be a potential strategy for the treatment of renal fibrosis. Randomized controlled trial studies with good methodological quality, favorable experimental design, and large sample size are needed to evaluate the efficacy and safety of Cordyceps.

Eosinophilic Granulomatosis With Polyangiitis Presenting With Oral Granuloma as the Initial Symptom: A Case Report.

Antineutrophil cytoplasmic antibody associated vasculitis includes granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis. While EGPA has no specific symptoms, it usually presents as necrotizing vasculitis, eosinophil infiltration of the tissues and organs, and extravascular granuloma formation. Here, we report a patient who had a rare initial presentation of oral granuloma and had been previously misdiagnosed several times at other hospitals. He was finally diagnosed with EGPA and recovered after methylprednisolone and cyclophosphamide treatment. The disease EGPA can present with a rare initial presentation of oral granuloma, methylprednisolone, and cyclophosphamide can be a suitable choice of treatment.

The C5a/C5aR1 Axis Contributes to the Pathogenesis of Acute Cystitis Through Enhancement of Adhesion and Colonization of Uropathogenic E. coli.

Our previous work using a murine model of pyelonephritis demonstrated that the C5a/C5aR1 axis plays a pathogenic role in acute kidney infection. In this study, we report that the C5a/C5aR1 axis also plays a pathogenic role in acute bladder infection. C5aR1-deficient mice had reduced bladder bacterial load and attenuated bladder tissue injury, which is associated with reduced expression of terminal α-mannosyl residues (Man) (a potential ligand for type 1 fimbriae of E. coli) at the luminal surface of the bladder epithelium and reduced early bacterial colonization of the bladder. In vitro, C5a stimulation enhanced mannose expression in and facilitated bacterial adhesion/colonization to human bladder epithelial cells. C5a stimulation also upregulated the activation of ERK1/2 and NF-κB signaling and gene expression of proinflammatory cytokines (i.e., Il6, Il1b, Cxcl1, Ccl2) in the epithelial cells, which could drive pro-inflammatory responses leading to tissue injury. Administration of the C5aR1 antagonist effectively reduced bladder bacterial load and tissue injury. Thus, our findings demonstrate a previously unknown pathogenic role for the C5a/C5aR1 axis in bladder infection and suggest that the C5a/C5aR1 axis-mediated upregulation of Man expression, enhancement of bacterial adhesion/colonization, and excessive inflammatory responses contribute to acute bladder infection. These findings improve our understanding of the pathogenesis of bladder infection with therapeutic implications for UTI.

LncRNA136131 suppresses apoptosis of renal tubular epithelial cells in acute kidney injury by targeting the miR-378a-3p/Rab10 axis.

The pathogenesis of acute kidney injury (AKI) is not fully understood. To date, the exact role and regulatory mechanism of long non-coding RNA (lncRNA)136131 in AKI remains unclear. Here, we demonstrate that lncRNA136131 in BUMPT cells is induced by antimycin A. Furthermore, after incubating BUMPT cells in antimycin for two hours, lncRNA136131 prevented BUMPT cell apoptosis and cleaved caspase-3 expression. Mechanistically, lncRNA136131 sponged miR-378a-3p and then increased the expression of Rab10 to suppress apoptosis. Finally, I/R-induced decline of renal function, tubular damage, renal tubular cells apoptosis, and the upregulation of cleaved caspase-3 were aggravated by lncRNA136131 siRNA. In contrast, this effect was attenuated by the overexpression of lncRNA136131. In conclusion, lncRNA136131 protected against I/R-induced AKI progression by targeting miR-378a-3p/Rab10 and may be utilized as a novel target for AKI therapeutics.

The Role of NLRP3 Inflammasome in IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide today. The NLRP3 inflammasome is a polyprotein complex and an important participant in inflammation. Accumulating studies have shown that the NLRP3 inflammasome participates in a variety of kidney diseases, including IgAN. This review focuses on the role of the NLRP3 inflammasome in IgAN and summarizes multiple involved pathways, which may provide novel treatments for IgAN treatment.

Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury.

Background and Objective: Acute kidney injury (AKI) is a complication of sepsis. Pyroptosis of gasdermin D (GSDMD)-mediated tubular epithelial cells (TECs) play important roles in pathogenesis of sepsis-associated AKI. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), an imprinted gene involved in tumorigenesis, is implicated in pyroptosis occurring in multiple organs. Herein, we investigated the role and mechanisms of MEG3 in regulation of TEC pyroptosis in lipopolysaccharide (LPS)-induced AKI. Materials and Methods: Male C57BL/6 mice and primary human TECs were treated with LPS for 24 h to establish the animal and cell models, respectively, of sepsis-induced AKI. Renal function was assessed by evaluation of serum creatinine and urea levels. Renal tubule injury score was assessed by Periodic acid-Schiff staining. Renal pyroptosis was assessed by evaluating expression of caspase-1, GSDMD, and inflammatory factors IL-1ß and IL-18. Cellular pyroptosis was assessed by analyzing the release rate of LDH, expression of IL-1ß, IL-18, caspase-1, and GSDMD, and using EtBr and EthD2 staining. MEG3 expression in renal tissues and cells was detected using RT-qPCR. The molecular mechanisms of MEG3 in LPS-induced AKI were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation, dual luciferase reporter gene assays, and a rescue experiment. Results: Pyroptosis was detected in both LPS-induced animal and cell models, and the expression of MEG3 in these models was significantly up-regulated. MEG3-knockdown TECs treated with LPS showed a decreased number of pyroptotic cells, down-regulated secretion of LDH, IL-1ß, and IL-18, and decreased expression of GSDMD, compared with those of controls; however, there was no difference in the expression of caspase-1 between MEG3 knockdown cells and controls. Bioinformatics analysis screened out miR-18a-3P, and further experiments demonstrated that MEG3 controls GSDMD expression by acting as a ceRNA for miR-18a-3P to promote TECs pyroptosis. Conclusion: Our study demonstrates that lncRNA MEG3 promoted renal tubular epithelial pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI.

Membranous nephropathy and thymoma in a patient with ankylosing spondylitis: A case report.

RATIONALE: We report a rare case with ankylosing spondylitis (AS), thymoma, and membranous glomerulonephritis. The pathogenic mechanisms of these 3 diseases may be associated with each other. Here, we discuss the course of diagnosis and treatment. PATIENT CONCERNS: A 64-year-old woman with bilateral pain of the sacroiliac joints for 10 years and anasarca for 10 days. DIAGNOSES: A diagnosis of AS by HLA-B27 and pelvic X-ray tests, thymoma based on computed tomography and pathological diagnosis, and membranous glomerulonephritis based on renal biopsy. INTERVENTIONS: We administered methylprednisolone 500 mg/d for 3 consecutive days, followed by methylprednisolone 40 mg oral QD, for a month. OUTCOMES: The patient was followed up once a month. In the sixth month, the patient's serum creatinine had decreased to 0.96 mg/dL, urine microalbumin/creatinine decreased to 173.3 mg/g, and albumin had risen to 33.1 g/L. Pain and morning stiffness were relieved, and the Bath Ankylosing Spondylitis Disease Activity Index score dropped to 4.0. LESSONS: Although the causal relationship between AS, thymoma, and membranous nephropathy in this patient still needs to be established, the pathogenesis between the 3 diseases may have some association. In clinical practice, patients with AS need to be screened for tumors and renal complications.

Disruption of Robo2-Baiap2 integrated signaling drives cystic disease.

Hereditary renal cystic diseases are characterized by defects in primary cilia of renal tubular epithelial cells and abnormality of tubular epithelium, which ultimately result in the development of renal cysts. However, the mechanism leading from abnormality of the tubular epithelium to cystogenesis is not well understood. In this report, we demonstrate a critical role for Robo2 in regulating epithelial development, including ciliogenesis, polarization, and differentiation. We found that Robo2 deficiency results in cystic kidneys, and the cyst cells showed defective cilia and polarity defects in tubular epithelium. The cyst cells, less than terminally differentiated, continue to proliferate. We further established that Robo2 works with p53 as well as polarity and ciliary proteins (Par3, PKCς, ZO-2, and Claudin-2) to regulate these processes. Robo2 binds to Baiap2 (also known as IRSp53) through the IRSp53/MIM homology domain in renal epithelial cells. This binding allows Robo2 to phosphorylate MDM2 at Ser166 via Baiap2 and maintain p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes MDM2 to be subjected to dephosphorylation, leading to a high level of active p53, and initiated p53-mediated cellular senescence via p21 and decreased the expression of ZO-1, ZO-2, PKCς, Par3, and Claudin-2 proteins, resulting in defects in epithelial development, including ciliogenesis, polarization, and differentiation. Importantly, double knockout of Robo2 and p53 rescued all the epithelial defects in kidneys compared with those in Robo2-knockout kidneys. Taken together, the present results demonstrate that Robo2 deficiency causes renal cystic disease, which is largely dependent on defective Robo2-Baiap2 integrated signaling in kidneys.

NMR-based metabolomic techniques identify potential urinary biomarkers for early colorectal cancer detection.

Better early detection methods are needed to improve the outcomes of patients with colorectal cancer (CRC). Proton nuclear magnetic resonance spectroscopy (1H-NMR), a potential non-invasive early tumor detection method, was used to profile urine metabolites from 55 CRC patients and 40 healthy controls (HCs). Pattern recognition through orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to 1H-NMR processed data. Model specificity was confirmed by comparison with esophageal cancers (EC, n=18). Unique metabolomic profiles distinguished all CRC stages from HC urine samples. A total of 16 potential biomarker metabolites were identified in stage I/II CRC, indicating amino acid metabolism, glycolysis, tricarboxylic acid (TCA) cycle, urea cycle, choline metabolism, and gut microflora metabolism pathway disruptions. Metabolite profiles from early stage CRC and EC patients were also clearly distinguishable, suggesting that upper and lower gastrointestinal cancers have different metabolomic profiles. Our study assessed important metabolomic variations in CRC patient urine samples, provided information complementary to that collected from other biofluid-based metabolomics analyses, and elucidated potential underlying metabolic mechanisms driving CRC. Our results support the utility of NMR-based urinary metabolomics fingerprinting in early diagnosis of CRC.

NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in patients with colorectal cancer.

Colorectal cancer (CRC) is a growing cause of mortality in developing countries, warranting investigation into its earlier detection for optimal disease management. A metabolomics based approach provides potential for noninvasive identification of biomarkers of colorectal carcinogenesis, as well as dissection of molecular pathways of pathophysiological conditions. Here, proton nuclear magnetic resonance spectroscopy (1HNMR) -based metabolomic approach was used to profile fecal metabolites of 68 CRC patients (stage I/II=20; stage III=25 and stage IV=23) and 32 healthy controls (HC). Pattern recognition through principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied on 1H-NMR processed data for dimension reduction. OPLS-DA revealed that each stage of CRC could be clearly distinguished from HC based on their metabolomic profiles. Successive analyses identified distinct disturbances to fecal metabolites of CRC patients at various stages, compared with those in cancer free controls, including reduced levels of acetate, butyrate, propionate, glucose, glutamine, and elevated quantities of succinate, proline, alanine, dimethylglycine, valine, glutamate, leucine, isoleucine and lactate. These altered fecal metabolites potentially involved in the disruption of normal bacterial ecology, malabsorption of nutrients, increased glycolysis and glutaminolysis. Our findings revealed that the fecal metabolic profiles of healthy controls can be distinguished from CRC patients, even in the early stage (stage I/II), highlighting the potential utility of NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in CRC patients.

Nocturnal and Circadian Rhythm of Blood Pressure Is Associated with Renal Structure Damage and Function in Patients with IgAN.

BACKGROUND AND AIMS: Abnormal circadian rhythm of blood pressure (BP) is closely related to target organ damage in hypertension. However, the association between abnormal circadian rhythm of BP and renal injury is not clear. We investigated whether renal injury is associated with nocturnal BP and circadian rhythm of BP in Chinese IgAN patients. METHODS: Clinic and 24 h ambulatory BP monitoring data were obtained from 330 Chinese IgAN patients with mean 24 h BP < 130/80 and mean daytime BP < 135/85 mmHg. Renal histopathological injury was determined according to the Oxford classification of IgAN. RESULTS: Among the 330 IgAN subjects, 35.8% suffered from nocturnal hypertension, 61.5% had abnormal circadian BP, and 27% had nocturnal hypertension with a nondipping pattern. Compared with nocturnal normotensive patients, patients with nocturnal hypertension had significantly higher levels of blood cystatin C, blood uric acid, and lower estimated glomerular filtration rate (eGFR), and significantly a higher mean renal tissue injury score. The nondipping hypertensive group had significantly higher nocturnal diastolic and systolic BP, blood uric acid, and glomerulosclerosis rates, whereas eGFR was lower. In nondipping hypertensive patients, urinary sodium excretion and renal tissue injury scores were significantly higher than dipping patients. Nocturnal hypertension and abnormal circadian BP correlated with renal tissue injury, renal interstitial fibrosis, and aortic arch atherosclerosis. CONCLUSION: Abnormal circadian rhythm of BP and nocturnal hypertension are common clinical manifestations in Chinese IgAN patients with normal mean 24 h BP. Abnormal circadian BP and nocturnal hypertension may accelerate IgAN progression by inducing renal dysfunction and histopathological damage.

Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy.

Premature senescence is an important event during diabetic nephropathy (DN) progression. Here, we investigated the role of endoplasmic reticulum (ER) stress-regulated activation of transcription factor 4 (ATF4)/p16 signaling in the premature senescence of renal tubular epithelial cells (RTECs) during DN development. In the renal tissues of Type 2 DN patients, we detected an increased number of senescent cells; elevated deposition of advanced glycation end products (AGEs); upregulated expression of ER stress marker, glucose-regulated protein 78; as well as overexpression of ATF4 and p16. Similarly, these phenomena were also observed in cultured mouse RTECs following AGE treatment. Interestingly, AGE-induced p16 expression and premature senescence were successfully attenuated by ER stress inhibitor and ATF4 gene silencing. Moreover, AGE-induced premature senescence was mimicked by ER stress inducers and ATF4 overexpression, while suppressed by p16 gene silencing. In addition, ER stress inducers can augment ATF4 expression. Therefore, our results demonstrate that the ER stress-regulated ATF4/p16 pathway is involved in the premature senescence of RTECs during DN progression.

miR-34a regulates mesangial cell proliferation via the PDGFR-ß/Ras-MAPK signaling pathway.

The main pathological characteristic of glomerulonephritis is diffuse mesangial cell proliferation. MiR-34a is associated with the proliferation of various organs and cancer cells. However, the role of miR-34a in renal proliferation diseases is not clear. Therefore, this study aimed to elucidate the mechanism of miR-34a in the regulation of renal mesangial cell proliferation. The miR-34a expression level at different time points in an anti-Thy1 mesangial proliferative nephritis rat model was determined by qRT-PCR. The cell proliferation rate and cell cycle changes were measured in the in vitro cultured rat mesangial cells (RMCs). Our results suggested that miR-34a expression was negatively correlated with the degree of cell proliferation in the anti-Thy1 nephritis model. MiR-34a could extend the G0/G1 phase and block cell proliferation in RMCs. Dual-luciferase assay results showed that there were binding sites of miR-34a at 3'-UTR of platelet-derived growth factor receptor-ß (PDGFR-ß). MiR-34a can inhibit PDGFR-ß protein expression at a post-transcriptional level, suppress Ras/MAPK signaling pathways, and down-regulate expression of cell cycle proteins at the G0/G1 phase, such as cyclin D1, CDK4/CDK6. In addition, miR-34a may also inhibit RMC proliferation by directly targeting cyclin E and CDK2. MiR-34a inhibits exogenous stimuli-induced proliferation of mesangial cells. Expression levels of phospho-PDGFR-ß and phospho-MEK1 (an important downstream molecule in PDGFR-ß-induced signaling pathway) were significantly increased in the anti-Thy-1 nephritis rat model. These results suggest that miR-34a may regulate RMC proliferation by directly inhibiting expressions of PDGFR-ß, MEK1, and cell cycle proteins, cyclin E and CDK2.