Search

Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition. [ABSTRACT FROM AUTHOR]

Hospital revisits significantly contribute to financial burden. Therefore, developing strategies to reduce hospital revisits is crucial for alleviating the economic impacts. However, this critical issue among peritoneal dialysis (PD) patients has not been explored in previous research. This single-center retrospective study, conducted at Chang Gung Memorial Hospital, Chiayi branch, included 1373 PD patients who visited the emergency room (ER) between Jan 2002 and May 2018. The objective was to predict hospital revisits, categorized into 72-h ER revisits and 14-day readmissions. Of the 1373 patients, 880 patients visiting the ER without subsequent hospital admission were analyzed to predict 72-h ER revisits. The remaining 493 patients, who were admitted to the hospital, were studied to predict 14-day readmissions. Logistic regression and decision tree methods were employed as prediction models. For the 72-h ER revisit study, 880 PD patients had a revisit rate of 14%. Both logistic regression and decision tree models demonstrated a similar performance. Furthermore, the logistic regression model identified coronary heart disease as an important predictor. For 14-day readmissions, 493 PD patients had a readmission rate of 6.1%. The decision tree model outperformed the logistic model with an area under the curve value of 79.4%. Additionally, a high-risk group was identified with a 36.4% readmission rate, comprising individuals aged 41 to 47 years old with a low alanine transaminase level ≤15 units per liter. In conclusion, we present a study using regression and decision tree models to predict hospital revisits in PD patients, aiding physicians in clinical judgment and improving care. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a serious public health problem. Due to a high variability in the speed of CKD progression to end-stage renal disease (ESRD) and the critical involvement of Wnt/β-catenin signaling in CKD, we investigated the role of the Wnt antagonist Dickkopf-1 (DKK1) in CKD progression. Our data revealed that patients with CKD stages 4–5 had higher DKK1 levels in their serum and renal tissues than the control subjects. In an 8-year follow-up, the serum DKK1-high group in the enrolled CKD patients showed a faster progression to ESRD than the serum DKK1-low group. Using a rat model of 5/6 nephrectomy (Nx)-induced CKD, we consistently detected elevated serum levels and renal production of DKK1 in 5/6 Nx rats compared to sham-operated rats. Importantly, the knockdown of the DKK1 levels in the 5/6 Nx rats markedly attenuated the CKD-associated phenotypes. Mechanistically, we demonstrated that the treatment of mouse mesangial cells with recombinant DKK1 protein induced not only the production of multiple fibrogenic proteins, but also the expression of endogenous DKK1. Collectively, our findings suggest that DKK1 acts as a profibrotic mediator in CKD, and elevated levels of serum DKK1 may be an independent predictor of faster disease progression to ESRD in patients with advanced CKD. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a complication of diabetes that leads to end-stage kidney disease and is a major health burden worldwide. Prenylflavonoid compounds extracted from Macaranga tanarius (MTE) exhibit anti-inflammation, anti-oxidant, and anti-bacterial properties. However, the effects of these compounds on diabetic nephropathy remain unclear. The effects of MTE on diabetic nephropathy were investigated in vitro by using mouse renal mesangial cells and in vivo by using a db/db knockout mouse model. No overt alteration in proliferation was observed in mouse renal mesangial cells treated with 0–1 μg/mL MTE. Western blot analysis indicated that MTE dose-dependently attenuated the expression of fibronectin, α-smooth muscle actin, and collagen IV. Administration of MTE ameliorated renal albumin loss in db/db mice. Immunohistochemical staining revealed that MTE mitigated diabetes-induced fibronectin and collagen IV expression. Periodic acid–Schiff (PAS) and trichrome staining also showed that administration of MTE reduced the renal fibrosis phenomenon. MTE significantly ameliorated diabetes-induced nephropathy. [ABSTRACT FROM AUTHOR]

Diabetes-induced chronic kidney disease leads to mortality and morbidity and thus poses a great health burden worldwide. Krüppel-like factor 10 (KLF10), a zinc finger-containing transcription factor, regulates numerous cellular functions, such as proliferation, differentiation, and apoptosis. In this study, we explored the effects of KLF10 on diabetes-induced renal disease by using a KLF10 knockout mice model. Knockout of KLF10 obviously diminished diabetes-induced tumor growth factor-β (TGF-β), fibronectin, and type IV collagen expression, as evidenced by immunohistochemical staining. KLF10 knockout also repressed the expression of Dickkopf-1 (DKK-1) and phosphorylated β-catenin in diabetic mice, as evidenced by immunohistochemical staining and Western blot analysis. Quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) revealed that significantly decreased type IV collagen, fibronectin, and DKK-1 existed in KLF10 knockout diabetic mice compared with control diabetic mice. Moreover, knockout of KLF10 reduced the renal fibrosis, as shown by Masson's Trichrome analysis. Overall, the results indicate that depletion of KLF10 ameliorated diabetic renal fibrosis via the downregulation of DKK-1 expression and inhibited TGF-β1 and phosphorylated β-catenin expression. Our findings suggest that KLF10 may be a promising therapeutic choice for the treatment of diabetes-induced renal fibrosis. [ABSTRACT FROM AUTHOR]

Arteriovenous graft (AVG) is an important vascular access route in hemodialysis patients. The optimal waiting time between AVG creation and the first cannulation is still undetermined, therefore the current study investigated the association between ideal timing for cannulation and AVG survival. This retrospective cohort study used data from the Taiwan National Health Insurance Database, which included 6,493 hemodialysis patients with AVGs between July 1st 2008 and June 30th 2012. The waiting cannulation time was defined as the time from the date of shunt creation to the first successful cannulation. Patients were categorized according to the waiting cannulation time of their AVGs as follows: ≤30 days, between 31 and 90 days, between 91 and 180 days, and >180 days. The primary outcome was functional cumulative survival, measured as the time from the first cannulation to shunt abandonment. The AVGs which were cannulated between 31 and 90 days (reference group) after construction had significantly superior functional cumulative survival compared with those cannulated ≤30 days (adjusted HR = 1.651 with 95% CI 1.482–1.839; p < 0.0001) and >180 days (adjusted HR = 1.197 with 95% CI 1.012–1.417; p = 0.0363) after construction. An analysis of the hazard ratios in patients with different demographic characteristics, revealed that the functional cumulative survival of AVGs in most groups was better when they received cannulation >30 days after construction. Consequently, in order to achieve the best long-term survival, AVGs should be cannulated at least 1 month after construction, but you should avoid waiting for >3 months. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is the leading cause of end‐stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up‐regulation of its downstream target KLF10. Overexpression of KLF10 in podocytes not only represses multiple podocyte‐specific markers including nephrin, but also conversely increases KDM6A expression. We further show that KLF10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM6A or KLF10 in mice significantly suppresses diabetes‐induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM6A and KLF10 proteins or mRNAs are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM6A–KLF10 feedback loop may be beneficial to attenuate diabetes‐induced kidney injury. Synopsis: Podocyte dysfunction is an early event in the development of diabetic nephropathy. This study reveals that activation of a KDM6A‐KLF10 positive feedback loop by hyperglycemia critically contributes to podocyte dysfunction. Blocking the KDM6A‐KLF10 signaling axis ameliorates diabetic kidney injury. Both KDM6A and KLF10 are up‐regulated in podocytes under diabetic conditions.Activation of the positive inter‐regulation between KDM6A and KLF10 results in repression of multiple podocyte‐specific marker proteins.Inactivation or podocyte‐specific knockout of KDM6A in mice attenuates diabetes‐induced kidney injury.Kidney injury is also reduced in KLF10‐knockout mice under diabetic conditions.Elevated levels of urinary exosomal KDM6A and KLF10 mRNAs are observed in human diabetic nephropathy patients relative to control subjects. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is one of the leading causes of end‐stage renal disease and creates heavy healthcare burdens globally. Dysfunction of mesangial cells and podocytes contributes to diabetic nephropathy. Dysregulation of signaling involved in renal development and regeneration may cause diabetic kidney damages. Growing evidences suggest the importance of dysregulated dickkopf‐1 (DKK1)/Wnt/ β‐catenin signaling pathways in the pathogenesis of diabetic glomerular injuries. The inhibition of Wnt signaling in injured mesangial cells is likely attributed to the high glucose‐induced Ras/Rac1 dependent superoxide formation. When DKK1, the cellular inhibitor of Wnt signaling, binds to the Kremen‐2 receptor, depositions of extracellular matrix increase in the mesangium of diabetic kidneys. Additionally, reactivation of Notch‐1 signaling has been implicated in podocytopathy during diabetic proteinuria development. Knocking down Notch‐1 alleviates vascular endothelial growth factor (VEGF) expression, nephrin repression and proteinuria in diabetic kidneys. It is also found that epigenetic modulations by histone deacetylase 4 (HDAC4) and miR‐29a could lead to diabetic nephropathy. High glucose increases the expression of HDAC4, which causes deacetylation with subsequent ubiquitination of nephrin. Overexpression of miR‐29a in diabetic transgenic mice would decrease the expression of HDAC4 and stabilize nephrin. Surprisingly, reprogramming or reactivation of signaling involved in renal development or regeneration often brings about diabetic glomerular sclerosis in mesangial cells and podocytes. Better knowledge about modifications of embryonic stem cell signaling will have a chance to implement strategically focused pharmacological research programs aiming to the development of new drugs for diabetic kidney injuries. Summary at a Glance: Dysregulation of signaling involved in renal development or regeneration often leads to diabetic nephropathy. Recent advances of these molecular mechanisms are discussed. [ABSTRACT FROM AUTHOR]

Introduction: Adiponectin (ADPN), one of most abundant fat-derived biologically active substances, plays an important role in anti-atherosclerotic process. There are conflicting results about the impact of ADPN on cardiovascular (CV) outcomes and mortality, particularly in patients undergoing peritoneal dialysis (PD). Moreover, the relationship between ADPN and inflammatory mediators has been seldom explored in this population. Therefore, we examined the relationship between ADPN and longitudinal high-sensitivity C-reactive protein (hs-CRP) changes and investigated whether ADPN or hs-CRP levels could predict CV outcomes and mortality in prevalent PD patients after comprehensive adjustment of possible confounders. Methods: In this prospective cohort study, 78 PD patients were enrolled and followed from February 2009 to August 2012. During follow-up, CV events and all-cause mortality were recorded. Results: The mean baseline ADPN value was 29.46±18.01 μg/ml and duration of PD treatment was 37.76±36.96 months. In multiple linear regression analysis, plasma ADPN levels positively correlated with high-density lipoprotein and negatively associated with hs-CRP, body mass index, D4/D0 glucose, triglyceride, and duration of PD treatment. After stratified by genders, the inverse association between baseline ADPN and hs-CRP was more significant in the female group. The hs-CRP levels were followed up annually and remained significantly lower in the high ADPN group in the first 2 years. Patients were then stratified into two groups according to the median ADPN value (23.8 μg/ml). The results of Kaplan-Meier survival analysis demonstrated less CV events and better survival in high ADPN group. On multivariate Cox regression analysis, only ADPN level (HR: 0.93, 95% CI: 0.88–0.98, p = 0.02), age and history of CV diseases were independent risk factors for future CV events. Furthermore, hs-CRP (HR: 1.11, 95% CI:1.001–1.22, p = 0.04) was identified as independent predictor of all-cause mortality. Conclusions: Serum hs-CRP levels were consistently lower in the high ADPN group during 2-year follow-up. We also demonstrated the importance of ADPN and hs-CRP in predicting CV events and all-cause mortality in PD population during 3.5-year follow-up. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is characterized by the development of progressive glomerulosclerotic lesions gradually leading to an increasing loss of functioning kidney parenchyma. Relatively little proteomic research of isolated glomeruli of experimental animal models has been done so far. Isolated glomerular proteomics is an innovative tool that potentially detects simultaneous expressions of glomeruli in diabetic pathological contexts. We compared the isolated glomerular profiles of rats with and without diabetes. The proteins in the aliquots of glomeruli were subjected to two-dimensional gel electrophoresis. The protein spots were matched and quantified using an imaging analysis system. The peptide mass fingerprints were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and a bioinformation search. We found that diabetes increased collagen type I and collagen type IV levels in diabetic glomeruli when compared to normal control group using Dynabeads. We found that rats with diabetes had significantly higher abundance of the Protein disulfide isomerase associated 3, Aspartoacylase-3,3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase, Lactamase beta 2 and Agmat protein. However, diabetic glomeruli in rats had significantly lower levels of the Regucalcin, rCG52140, Aldo-keto reductase family 1, Peroxiredoxin 1, andl-arginine: glycine amidinotransferase. These proteins of interest were reported to modulate disturbances in the homeostasis of endoplasmic reticulum stress, disturbance of inflammatory and fibrinogenic activities, impairing endothelial function, and dysregulation in the antioxidation capacity/oxidative stress in several tissue types under pathological contexts. Taken together, our high-throughput isolated glomerular proteomic findings indicated that multiple pathological reactions presumably occurred in DN. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a world-wide public health problem. The purpose of this study was to identify the role of some controversial potential risk factors in development of CKD. 'Community Complex Health Screening' is a large-scale, free, health program for individuals ≥40 years of age that has been available since January 2002 in Chiayi County, Taiwan. A questionnaire was administered to study participants, collecting information on ethnicity, use of analgesics, and life habits. Age, sex, and blood biochemical analyses were considered as potential confounders. A high prevalence and low awareness of CKD were noted in this population. Females with CKD had a lower awareness of their illness than males. Analgesic users had a significantly lower estimated glomerular filtration rate (eGFR). Age (OR = 1.095), females (OR = 0.348), fasting plasma glucose (OR = 1.005), level of uric acid (UA) (OR = 1.517), and analgesic usage (OR = 1.512) remained independent predictors of CKD. Multivariate linear regression found that use of analgesics, father' clan from Fujian, mother' clan from Fujian, and coffee intake were independent determinants of renal outcome with coefficient of regression (β) of −0.102, −0.192, 0.210 and 0.88, respectively. The prevalence of CKD decreased with advanced education. Further, there was no significant difference between education background and analgesics use. In conclusion, analgesic use, parents' clan, and coffee intake were independent risk factors for CKD in middle-aged and elderly Taiwanese. Thus, an effective educational program that increases the awareness of such individuals residing in rural counties is warranted. [ABSTRACT FROM AUTHOR]

Background: Nephrologist-based multidisciplinary care (MDC) has a positive impact on slowing chronic kidney disease (CKD) progression. However, the benefits of MDC in patients with stage 5 CKD remain unclear. Methods: Stage 5 CKD patients who visited the Chang Gung Memorial Hospital, Chiayi, Taiwan during the period of 2002-2008 were enrolled. The incident dialysis and medical cost were compared between MDC recipients and nonrecipients. The MDC recipients were divided into two groups by educational duration to observe the clinical renal outcome and medical care expenses. The effect of MDC on renal disease progression was also compared in MDC recipients with and without diabetes. Results: Out of 307 patients, 171 received MDC. For MDC recipients, the temporary usage of catheter was reduced (54.7% vs. 79.4%, p < 0.001), the hospital stay was shorter (18.64 ± 1.20 vs. 24.63 ± 1.22 months, p = 0.001), and the total medical cost was lower [New Taiwan dollars (NTD) 105,948.54 ± 9,967.22 vs. NTD 160,388.61 ± 16,373.97, p = 0.005] than for nonrecipients. Out of the 171 MDC recipients, those with MDC for more than 1 year had slower renal disease progression (0.76 ± 0.27 mL/min per 1.73 m2 per year) and had an estimated per- capita annual cost savings of about NTD 336,500.66. MDC recipients with diabetes had a higher risk of requiring dialysis than those without diabetes. Conclusions: MDC could significantly reduce temporary use of the catheter, hospital stay, and total medical costs in patients with stage 5 CKD. Furthermore, longer (>1 year) MDC could preserve renal function and deliver annual medical cost savings. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a hallmark event in the pathogenesis of diabetic nephropathy. Considerable evidence now supports that multiple intracellular signaling pathways are critically involved in renal fibrosis. Previously, our studies have shown that dysregulation of the MicroRNA 29a (miR-29a)- or cannabinoid type 1 receptor (CB1R)-mediated signaling cascade in renal glomeruli substantially contributes to diabetic renal fibrosis. The purpose of the current study was to explore whether curcumin, a natural polyphenolic compound with potential renoprotective activity, could modulate the miR-29a/CB1R signaling axis to attenuate renal fibrosis. In this study, rat renal mesangial cells cultured in high glucose (HG) and the diabetic db/db mice were used as an in vitro and in vivo model of diabetes, respectively. Our results showed that in rat renal mesangial cells, curcumin treatment substantially counteracted HG-induced changes in the expressions of miR-29a, CB1R, peroxisome proliferator-activated receptor gamma (PPAR-γ), and a profibrotic marker type IV collagen (collagen IV), as assessed by quantitative Real-Time Polymerase chain reaction (RT-PCR). Furthermore, in the db/db mouse model, administration of curcumin markedly lowered urinary albumin excretion, and reduced deposition of extracellular matrices including collagen IV in renal tissues. Importantly, quantitative RT-PCR, in situ hybridization, and immunohistochemical analysis revealed that curcumin treatment consistently blocked diabetes-induced downregulation of miR-29a and upregulation of CB1R in renal glomeruli. Collectively, our study provides novel evidence showing that curcumin can rescue the dysregulated miR-29a/CB1R signaling pathway in glomerular mesangium to ameliorate diabetic renal fibrosis. [ABSTRACT FROM AUTHOR]

(1) Background: A functional shunt is critical to hemodialysis, but the ideal timing of shunt cannulation is still not established. In this study, we assessed the association between ideal puncture timing and shunt survival. (2) Methods: This retrospective cohort study using data from the Taiwan Health and Welfare database, which included 26885 hemodialysis patients with arteriovenous fistulas from 1 July 2008 to 30 June 2012. Fistulas were categorized by functional maturation time, defined as the time from the date of shunt construction to the first successful cannulation. Functional cumulative survival, measured as the duration from the first puncture to shunt abandonment, was mainly regarded. (3) Results: The fistulas created between 91 and 180 days prior to the first cannulation had significantly greater cumulative functional survival (HR 0.883; 95% CI 0.792–0.984), and there was no more benefit on their survival from waiting more than 180 days (HR 0.957; 95% CI 0.853–1.073) for shunt maturity. (4) Conclusions: Our results showed that to achieve better long-term shunt survivals, fistulas should be constructed at least 90 days before starting hemodialysis. Notably, there was no additional benefit on waiting more than 180 days prior to cannulation. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy often leads to end-stage renal disease and life-threatening morbidities. Simple control of risk factors is insufficient to prevent the progression of diabetic nephropathy, hence the need for discovering new treatments is of paramount importance. Recently, the dysregulation of microRNAs or the cannabinoid signaling pathway has been implicated in the pathogenesis of various renal tubulointerstitial fibrotic damages and thus novel therapeutic targets for chronic kidney diseases have emerged; however, the role of microRNAs or cannabinoid receptors on diabetes-induced glomerular injuries remains to be elucidated. In high-glucose-stressed renal mesangial cells, transfection of a miR-29a precursor sufficiently suppressed the mRNA and protein expressions of cannabinoid type 1 receptor (CB1R). Our data also revealed upregulated CB1R, interleukin-1β, interleukin-6, tumor necrosis factor-α, c-Jun, and type 4 collagen in the glomeruli of streptozotocin (STZ)-induced diabetic mice, whereas the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) was decreased. Importantly, using gain-of-function transgenic mice, we demonstrated that miR-29a acts as a negative regulator of CB1R, blocks the expressions of these proinflammatory and profibrogenic mediators, and attenuates renal hypertrophy. We also showed that overexpression of miR-29a restored PPAR-γ signaling in the renal glomeruli of diabetic animals. Collectively, our findings indicate that the interaction between miR-29a, CB1R, and PPAR-γ may play an important role in protecting diabetic renal glomeruli from fibrotic injuries. [ABSTRACT FROM AUTHOR]

Tubulointerstitial fibrosis is a major pathological hallmark of diabetic nephropathy. Increasing evidence has shown that epithelial-to-mesenchymal transition (EMT) of renal proximal tubular cells plays a crucial role in tubulointerstitial fibrosis. Herein, we aimed to elucidate the detailed mechanism of EMT in renal tubular cells under high glucose (HG) conditions, and to investigate the potential of licorice, a medicinal herb, to inhibit HG-induced EMT. Our results showed that renal tubular epithelial cells (normal rat kidney cell clone 52E; NRK-52E) exposed to HG resulted in EMT induction characterized by increased fibronectin and -SMA (alpha-smooth muscle actin) but decreased E-cadherin. Elevated levels of cleaved Notch2, MAML-1 (mastermind-like transcriptional coactivator 1), nicastrin, Jagged-1 and Delta-like 1 were also concomitantly detected in HG-cultured cells. Importantly, pharmacological inhibition, small interfering RNA (siRNA)-mediated depletion or overexpression of the key components of Notch2 signaling in NRK-52E cells supported that the activated Notch2 pathway is essential for tubular EMT. Moreover, we found that licorice extract (LE) with or without glycyrrhizin, one of bioactive components in licorice, effectively blocked HG-triggered EMT in NRK-52E cells, mainly through suppressing the Notch2 pathway. Our findings therefore suggest that Notch2-mediated renal tubular EMT could be a therapeutic target in diabetic nephropathy, and both LE and de-glycyrrhizinated LE could have therapeutic potential to attenuate renal tubular EMT and fibrosis., Competing Interests: The authors declare no conflict of interest. Moreover, the funders had no role in the design of the study; the collection, analysis, or interpretation of data; in the writing of the manuscript, or the decision to publish the results.

Renal fibrosis is the final common pathological feature in a variety of chronic kidney disease. Trichostatin A (TSA), a histone deacetylase inhibitor, reportedly attenuates renal fibrosis in various kidney disease models. However, the detailed molecular action of TSA in ameliorating renal fibrotic injury is not yet fully understood. In a cultured renal fibroblastic cell model, we showed that TGF-β1 triggers upregulation of α-SMA and fibronectin, two hallmarks of myofibroblastic activation. During the course of TGF-β1 treatment, activation of Smad2/3, p38, ERK, JNK and Notch-2 was also detected. Under the conditions, administration of TSA significantly decreased TGF-β1-stimulated expression of α-SMA, fibronectin, phospho-JNK, and cleaved Notch-2; however, the levels of phospho-Smad2/3, phospho-p38 and phospho-ERK remained unchanged. Pharmacological inhibition of different signaling pathways and genetic knockdown of Notch-2 further revealed JNK as an upstream effector of Notch-2 in TGF-β1-mediated renal fibrosis. Consistently, we also demonstrated that administration of TSA or a γ-secretase inhibitor RO4929097 in the mouse model of unilateral ureteral obstruction significantly ameliorated renal fibrosis through suppression of the JNK/Notch-2 signaling activation. Taken together, our findings provide further insights into the crosstalk among different signaling pathways in renal fibrosis, and elucidate the molecular action of TSA in attenuating fibrogenesis.