Aims/hypothesis
The contribution of aberrantly expressed microRNAs (miRNAs) to diabetic nephropathy in vivo is poorly understood.
Methods
Integrated comparative miRNA array profiling was used to ...examine the expression of serum miRNAs in patients with diabetic nephropathy. The abundance of miRNA-135a (miR-135a) was measured by real-time quantitative PCR in the serum and kidney tissues of patients with diabetic nephropathy. The luciferase assay combined with mutation and immunoblotting was used to screen and verify the bioinformatically predicted miRNAs. Ca
2+
entry or intracellular Ca
2+
(Ca
2+
i
) was performed by imaging Fura-2/AM-loaded cells using a fluorescence microscopy system. The role of miR-135a in vivo was explored with locked nucleic acid antisense oligonucleotides.
Results
MiR-135a was markedly upregulated in serum and renal tissue from patients with diabetic nephropathy, as well from
db/db
mice, and this was associated with the development of microalbuminuria and renal fibrosis. Furthermore, we identified transient receptor potential cation channel, subfamily C, member 1 (
TRPC1
) as a target of miR-135a during renal injury. We demonstrated that overexpression of TRPC1 was able to reverse the pathological effects of miR-135a on promoting proliferation of mesangial cells and increasing synthesis of extracellular matrix proteins. Moreover, miR-135a attenuated store depletion-induced Ca
2+
entry into cells by regulating TRPC1. Importantly, knockdown of miR-135a in diabetic kidneys restored levels of TRPC1 and reduced synthesis of fibronectin and collagen I in vivo. Suppressing TRPC1 levels to prevent Ca
2+
entry into cells may be a mechanism whereby miR-135a promotes renal fibrosis in diabetic kidney injury.
Conclusions/interpretation
These findings suggest an important role for miR-135a in renal fibrosis and inhibition of miR-135a might be an effective therapy for diabetic nephropathy.
The outgrowth of epithelial bud followed by reiterated bifurcations during renal development is driven by the ligand-receptor interactions between the epithelium and the surrounding mesenchyme. Here, ...by exploring ligand-receptor interactions in E10.5 and E11.5 kidneys by single cell RNA-seq, we find that Isthmin1 (Ism1), a secreted protein, resembles Gdnf expression and modulates kidney branching morphogenesis. Mice deficient for Ism1 exhibit defective ureteric bud bifurcation and impaired metanephric mesenchyme condensation in E11.5 embryos, attributable to the compromised Gdnf/Ret signaling, ultimately leading to renal agenesis and hypoplasia/dysplasia. By HRP-induced proximity labelling, we further identify integrin α8β1 as a receptor of Ism1 in E11.5 kidney and demonstrate that Ism1 promoted cell-cell adhesion through interacting with Integrin α8β1, the receptor whose activation is responsible for Gdnf expression and mesenchyme condensation. Taken together, our work reveals Ism1 as a critical regulator of cell-cell interaction that modulates Gdnf/Ret signaling during early kidney development.
Previous studies have indicated that the performance of glomerular filtration rate (GFR) estimation equations vary according to the races of the target population. The Chronic Kidney Disease ...Epidemiology Collaboration (CKD-EPI) equation has not been validated in the Chinese population including patients with chronic kidney disease (CKD) and healthy controls.
A total of 977 adult persons (682 patients with CKD and 295 healthy volunteers) from nine renal institutes of university hospitals located in nine geographic regions of China were enrolled in the study. A diagnostic test study comparing the CKD-EPI two-level and four-level race equation, the Modification of Diet in Renal Disease (MDRD) Study equation and the modified MDRD equation for Chinese (the Chinese equation). The (99m)Tc- diethylenetriamine pentaacetic acid dual plasma clearance was used as a reference method for measuring GFR.
The mean age of participants was 48.3 ± 16.0 years and 479 (49.0%) were male. The CKD-EPI two-level race equation and the Chinese equation performed better than the MDRD Study equation and CKD-EPI four-level race equation, with less bias (median difference between estimated GFR and reference GFR, 0.2 and 0.3 versus -2.4 and 3.0 mL/min/1.73 m(2)), improved precision (interquartile range of the difference, 20.5 and 20.8 versus 23.4 and 20.5 mL/min/1.73 m(2)) and greater accuracy (percentage of estimated GFR within 30% of reference GFR, 73.4 and 73.0% versus 69.8 and 70.1%).
The CKD-EPI two-level race equation and the Chinese equation performed similarly in the Chinese population, and both performed better than the MDRD Study equation and the CKD-EPI four-level race equation.
Results concerning the association between peritoneal dialysis-related peritonitis and mortality in peritoneal dialysis patients are inconclusive, with one potential reason being that the ...time-dependent effect of peritonitis has rarely been considered in previous studies. This study aimed to evaluate whether peritonitis has a negative impact on mortality in a large cohort of peritoneal dialysis patients. We also assessed the changing impact of peritonitis on patient mortality with respect to duration of follow-up.
This retrospective cohort study included incident patients who started peritoneal dialysis from 1 January 2006 to 31 December 2011. Episodes of peritonitis were recorded at the time of onset, and peritonitis was parameterized as a time-dependent variable for analysis. We used the Cox regression model to assess whether peritonitis has a negative impact on mortality.
A total of 1321 patients were included. The mean age was 48.1 ± 15.3 years, 41.3% were female, and 23.5% with diabetes mellitus. The median (interquartile) follow-up time was 34 (21-48) months. After adjusting for confounders, peritonitis was independently associated with 95% increased risk of all-cause mortality (hazard ratio, 1.95; 95% confidence interval: 1.46-2.60), 90% increased risk of cardiovascular mortality (hazard ratio, 1.90; 95% confidence interval: 1.28-2.81) and near 4-fold increased risk of infection-related mortality (hazard ratio, 4.94; 95% confidence interval: 2.47-9.86). Further analyses showed that peritonitis was not significantly associated with mortality within 2 years of peritoneal dialysis initiation, but strongly influenced mortality in patients dialysed longer than 2 years.
Peritonitis was independently associated with higher risk of all-cause, cardiovascular and infection-related mortality in peritoneal dialysis patients, and its impact on mortality was more significant in patients with longer peritoneal dialysis duration.
Peritoneal fibrosis is a major cause of ultrafiltration failure in patients receiving continuous ambulatory peritoneal dialysis. Transforming growth factor (TGF)-β1 is an important mediator in this ...process; however, its signaling mechanisms had not been explored. Thus, we examined TGF-β1/Smad signaling in human peritoneal biopsy specimens associated with continuous ambulatory peritoneal dialysis. We found that TGF-β/Smad2/3 signaling was highly activated in patients with increased collagen deposition and thickening of the peritoneal membrane who were receiving continuous ambulatory peritoneal dialysis. Long-term exposure of wild-type mice to 4.25% peritoneal dialysis solution for 30 days induced significant peritoneal fibrosis with impaired peritoneal equilibrium, which was prevented in Smad3 knockout mice. In contrast, conditional Smad2 gene deletion in the peritoneum exacerbated peritoneal fibrosis and dysfunction. The contrasting roles of Smad2 and Smad3 in peritoneal fibrosis were also examined in vitro . Cultured mesothelial cells from Smad3 knockout mice were resistant to TGF-β1–induced collagen I production and the transition toward a myofibroblast phenotype as seen in wild-type cells, whereas Smad2 deficiency in mesothelial cells failed to modulate the profibrotic response to TGF-β1. In conclusion, this study found activation of TGF-β/Smad signaling in peritoneal fibrosis in patients receiving continuous ambulatory peritoneal dialysis and identifies opposing roles for Smad2 and Smad3 in peritoneal dialysis–associated peritoneal fibrosis. These findings provide a mechanistic basis for future therapies targeting TGF-β/Smad signaling in peritoneal fibrosis.
Background Intravenous cyclophosphamide with prednisone is an effective treatment for lupus nephritis, but with significant toxicities. We compared the efficacy and safety of tacrolimus versus ...intravenous cyclophosphamide as induction therapy. Study Design Multicenter noninferiority randomized controlled trial. Setting & Participants 81 patients with biopsy-proven lupus nephritis from 9 nephrology centers in China from 2006-2008. Intervention Prednisone and either tacrolimus (n = 42) or intravenous cyclophosphamide (n = 39) for 6 months. Tacrolimus was started at 0.05 mg/kg/d and titrated to achieve a trough blood concentration of 5-10 ng/mL. Intravenous cyclophosphamide was initiated at 750 mg/m2 of body surface area, then adjusted to 500-1,000 mg/m2 every 4 weeks for a total of 6 pulse treatments. Outcomes & Measurements The primary outcome was complete remission (proteinuria with protein excretion <0.3 g/24 h, serum albumin ≥3.5 g/dL, normal urinary sediment, and normal or stable serum creatinine level) at 6 months. Response (complete or partial remission), clinical parameters, and adverse effects were secondary end points. Results After the 6-month induction therapy, the tacrolimus group achieved higher cumulative probabilities of complete remission and response (52.4% vs 38.5% and 90.5% vs 82.1%, respectively) than the intravenous cyclophosphamide group, but differences were not statistically significant (log-rank test, P = 0.2 and P = 0.7, respectively). Proteinuria (log-transformed) was significantly decreased in tacrolimus- versus intravenous cyclophosphamide–treated patients after the first month of treatment, even with adjustment for baseline proteinuria (protein excretion, 0.01 vs 0.23 g/d; P = 0.02). After treatment, serum creatinine levels and estimated glomerular filtration rates were not significantly different between treatment groups. Adverse effects, such as leukopenia and gastrointestinal symptoms, were less frequent in the tacrolimus group. Limitations Nonblinded, small sample size, and short duration of follow-up. Conclusions In conjunction with prednisone, induction therapy with tacrolimus is at least as efficacious as intravenous cyclophosphamide and prednisone in producing complete remission of lupus nephritis and has a more favorable safety profile.
Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue ...(WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.
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•Mast cells in WAT from lean humans and mice are leptin deficient•Reconstitution of leptin-deficient mast cells mitigates obesity and diabetes in mice•Leptin-deficient mast cells promote M2 macrophage polarization•Leptin-deficient mast cells slant anti-inflammatory signaling in response to leptin
Proinflammatory mast cells play detrimental roles in obesity and diabetes. Zhou et al. show that mast cells in white adipose tissues from lean humans and mice are leptin deficient and polarize macrophages toward anti-inflammatory M2 phenotype. Adoptive transfer of leptin-deficient mast cells mitigates obesity and diabetes in obese mice.
Objective. To compare the efficacy and safety of mycophenolate mofetil (MMF) and intravenous cyclophosphamide (IVC) as induction treatment for lupus nephritis (LN), by race, ethnicity and ...geographical region. Methods. A total of 370 patients with active Class III–V LN received MMF (target dose 3.0 g/day) or IVC (0.5–1.0 g/m2/month), plus tapered prednisone, for 24 weeks. Renal function, global disease activity, immunological complement (C3 and C4) and anti-dsDNA levels are the outcomes that were assessed in this study. Results. MMF was not superior to IVC as induction treatment (primary objective). There were important pre-specified interactions between treatment and race (P = 0.047) and treatment and region (P = 0.069) (primary endpoint). MMF and IVC response rates were similar for Asians (53.2 vs 63.9%; P = 0.24) and Whites (56.0 vs 54.2%; P = 0.83), but differed in the combined Other and Black group (60.4 vs 38.5%; P = 0.03). Fewer patients in the Black (40 vs 53.9%; P = 0.39) and Hispanic (38.8 vs 60.9%; P = 0.011) groups responded to IVC. Latin American patients had lower response to IVC (32 vs 60.7%; P = 0.003). Baseline disease characteristics were not predictive of response. The incidence of adverse events (AEs) was similar across groups. Serious AEs were slightly more prevalent among Asians. Conclusions. MMF and IVC have similar efficacy overall to short-term induction therapy for LN. However, race, ethnicity and geographical region may affect treatment response; more Black and Hispanic patients responded to MMF than IVC. As these factors are inter-related, it is difficult to draw firm conclusions about their importance. Trial registration. National Institutes of Health, www.clinicaltrials.gov, registration number NCT00377637.
Though the roles of microRNAs (miRNAs) in renal diseases have been extensively investigated, a thorough screening and comparison of miRNAs among different types of chronic kidney disease (CKD) has ...never been performed.
The intrarenal miRNAs were profiled from fresh kidney tissues of patients with biopsy-proven minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS) and diabetic nephropathy (DN) by using microarray. Commonly dysregulated miRNAs were validated by real-time PCR using paraffin-embedded renal tissues from all three types of CKD patients as well as mouse unilateral ureteral obstruction (UUO) model. Two novel miRNAs were selected and annotations of their target genes were performed using GO and KEGG pathway enrichment analysis. Biological functions of three two candidate miRNAs were explored in TGF-β1-induced cell model using human kidney proximal tubular cells (HK-2).
The kidney biopsy samples of three disease types represent different levels of damage and fibrosis, which were the mildest in MCD, moderate in FSGS, and the most severe in DN. 116 miRNAs were identified to be commonly dysregulated, including 40 up-regulated and 76 down-regulated in CKD tissues as compared with healthy donor kidney biopsy tissues. Two novel miRNAs, hsa-miR-3607-3p and hsa-miR-4709-3p, were verified as consistently differentially expressed among all three types of patient samples as well as in mouse model. In vitro, hsa-miR-3607-3p was repressed while hsa-miR-4709-3p was induced by TGF-β1 treatment. Inhibition of hsa-miR-3607-3p or overexpression of hsa-miR-4709-3p promoted TGF-β1-induced migration and F-actin assembling in HK-2 cells, which are characteristics of epithelial-mesenchymal transition (EMT). Further study identified that ITGB8 and CALM3 were the bona fide target genes of hsa-miR-3607-3p and hsa-miR-4709-3p respectively.
The present identify a unique miRNAs profile that probably relates to the common fibrosis process of CKD. Results of our study suggest that hsa-miR-3607-3p and hsa-miR-4709-3p may represent as promising therapeutic targets against kidney fibrosis.
♦
Fluid overload is frequently present in dialysis patients and one of the important predictors of patient outcome. This study aimed to investigate the influence of fluid overload on all-cause ...mortality and technique failure in Southern Chinese continuous ambulatory peritoneal dialysis (CAPD) patients. ♦
This was a post hoc study from a cross-sectional survey originally designed to investigate the prevalence and associated risk factors of fluid overload defined by bioimpedance analysis (BIA) in CAPD patients from January 1, 2008, to December 31, 2009. All 307 CAPD patients completing the original study were followed up until December 31, 2012. ♦
With a median follow-up period of 38.4 (19.2 - 47.9) months, 52 patients died. Patients with fluid overload (defined by extracellular water/total body water ECW/TBW ≥ 0.40) had a significantly higher peritonitis rate (0.016 vs 0.011 events/month exposure, p = 0.018) and cerebrovascular event rate (3.9 vs 1.1 events/100 patient years, p = 0.024) than the normal hydrated patients. Moreover, the results showed a significant rising of all-cause mortality (log-rank test = 5.59, p = 0.018), and a trend of increasing cardiovascular disease (CVD) mortality (log-rank test = 2.90, p = 0.089) and technique failure (log-rank test = 3.78, p = 0.052) in the patients with fluid overload. Fluid overload independently predicted all-cause mortality (hazard ratio HR = 12.98, 95%, confidence interval CI = 1.06 - 168.23, p = 0.042) and technique failure (HR = 13.56, 95% CI = 2.53 - 78.69, p = 0.007) in CAPD patients after adjustment for confounders. ♦
Fluid overload defined by BIA was an independent predictor for all-cause mortality and technique failure in CAPD patients. Continuous ambulatory peritoneal dialysis patients with fluid overload had a higher peritonitis rate, cardiovascular event rate, and poorer clinical outcome than those patients with normal hydration.
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