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Diabetic nephropathy, a leading cause of end-stage renal disease, accounts for significant morbidity and mortality. It is characterized by microinflammation in the glomeruli and myofibroblast activation in the tubulointerstitium. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, is shown to possess anti-inflammatory and anti-fibrotic properties, implying its renal-protective potential. This study investigates which type of component can reduce the damage caused by diabetic nephropathy in a single setting. The ethyl acetate (EtOAc) layer was demonstrated to provoke peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ activities in renal mesangial cells by dual luciferase reporter assay. In a high glucose (HG)-cultured mesangial cell model, the EtOAc layer substantially inhibited HG-induced elevations of interleukin-1β, transforming growth factor-β1 (TGF-β1), and fibronectin, whereas down-regulated PPAR-γ was restored. In addition, among the extracts of S. miltiorrhiza, the EtOAc layer effectively mitigated TGF-β1-stimulated myofibroblast activation. The EtOAc layer also showed a potent ability to attenuate renal hypertrophy, proteinuria, and fibrotic severity by repressing diabetes-induced proinflammatory factor, extracellular matrix accumulation, and PPAR-γ reduction in the STZ-induced diabetes mouse model. Our findings, both in vitro and in vivo, indicate the potential of the EtOAc layer from S. miltiorrhiza for future drug development targeting diabetic nephropathy. [ABSTRACT FROM AUTHOR]

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]

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular complications of DM are the leading cause of morbidity and mortality in diabetic patients. There are three major types of pathophysiologic cardiac remodeling including coronary artery atherosclerosis, cardiac autonomic neuropathy, and DM cardiomyopathy in patients with DM. DM cardiomyopathy is a distinct cardiomyopathy characterized by myocardial dysfunction in the absence of coronary artery disease, hypertension, and valvular heart disease. Cardiac fibrosis, defined as the excessive deposition of extracellular matrix (ECM) proteins, is a hallmark of DM cardiomyopathy. The pathophysiology of cardiac fibrosis in DM cardiomyopathy is complex and involves multiple cellular and molecular mechanisms. Cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction (HFpEF), which increases mortality and the incidence of hospitalizations. As medical technology advances, the severity of cardiac fibrosis in DM cardiomyopathy can be evaluated by non-invasive imaging modalities such as echocardiography, heart computed tomography (CT), cardiac magnetic resonance imaging (MRI), and nuclear imaging. In this review article, we will discuss the pathophysiology of cardiac fibrosis in DM cardiomyopathy, non-invasive imaging modalities to evaluate the severity of cardiac fibrosis, and therapeutic strategies for DM cardiomyopathy. [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]

Redox is a constant phenomenon in organisms. From the signaling pathway transduction to the oxidative stress during the inflammation and disease process, all are related to reduction-oxidation (redox). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor targeting many antioxidant genes. In non-stressed conditions, NRF2 maintains the hemostasis of redox with housekeeping work. It expresses constitutively with basal activity, maintained by Kelch-like-ECH-associated protein 1 (KEAP1)-associated ubiquitination and degradation. When encountering stress, it can be up-regulated by several mechanisms to exert its anti-oxidative ability in diseases or inflammatory processes to protect tissues and organs from further damage. From acute kidney injury to chronic kidney diseases, such as diabetic nephropathy or glomerular disease, many results of studies have suggested that, as a master of regulating redox, NRF2 is a therapeutic option. It was not until the early termination of the clinical phase 3 trial of diabetic nephropathy due to heart failure as an unexpected side effect that we renewed our understanding of NRF2. NRF2 is not just a simple antioxidant capacity but has pleiotropic activities, harmful or helpful, depending on the conditions and backgrounds. [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]

Diabetic kidney disease (DKD) frequently leads to end-stage renal disease and other life-threatening illnesses. The dysregulation of glomerular cell types, including mesangial cells, endothelial cells, and podocytes, appears to play a vital role in the development of DKD. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory and anti-inflammatory properties through the depletion of L-arginine that is required by T cells, through generation of oxidative stress, interference with T-cell recruitment and viability, proliferation of regulatory T cells, and through the promotion of pro-tumorigenic functions. Under hyperglycemic conditions, mouse mesangial cells reportedly produce higher levels of fibronectin and pro-inflammatory cytokines. Moreover, the number of MDSCs is noticeably decreased, weakening inhibitory immune activities, and creating an inflammatory environment. In diabetic mice, immunotherapy with MDSCs that were induced by a combination of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1β, and IL-6, reduced kidney to body weight ratio, fibronectin expression, and fibronectin accumulation in renal glomeruli, thus ameliorating DKD. In conclusion, MDSCs exhibit anti-inflammatory activities that help improve renal fibrosis in diabetic mice. The therapeutic targeting of the proliferative or immunomodulatory pathways of MDSCs may represent an alternative immunotherapeutic strategy for DKD. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) can cause inflammation and fibrosis, in addition to being the main complication of diabetes. Among many factors, epigenetic alterations in aberrant histone modifications play a key role in causing DKD. In this study, the mechanism of GSK-J4, a histone demethylase KDM6A inhibitor, was evaluated in streptozotocin-induced diabetic mice. It was confirmed that GSK-J4, via dickkopf-1 (DKK1) modulation, could significantly reduce proteinuria and glomerulosclerosis in diabetic mice. The mRNA accumulation levels of DKK1, TGF-β1, fibronectin, and collagen IV were significantly elevated in diabetic mice. In contrast, the mRNA accumulations of those genes were significantly reduced in diabetic mice treated with GSK-J4 compared to those in diabetic mice, relatively speaking. The protein accumulation levels of fibronectin and collagen IV were significantly elevated in diabetic mice. Furthermore, GSK-J4 attenuated the high glucose-induced expression of profibrotic factors in mesangial cells via DKK1. In conclusion, our study provides a novel strategy to eliminate fibrosis in the kidneys of DKD mice. Using GSK-J4 reduces DKK1 expression, thereby ameliorating renal insufficiency, glomerulosclerosis morphological abnormalities, inflammation, and fibrosis in diabetic mice. [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]

Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system's role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD. [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.