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BackgroundThis study retrospectively evaluated the actual efficacy of Kangxian Yanshen Formula Chinese medicine on renal function-related indicators in chronic kidney disease (CKD) stage 3–4 patients.MethodsIn this retrospective cohort study, we collected 212 adult CKD patients with baseline estimated glomerular filtration rate (eGFR) of 15–60 ml/min/1.73 m2. All participants received usual care (i.e., Western medications), and participants in the exposure group (n = 109) were additionally prescribed Kangxian Yanshen Formula Chinese medicine. The primary outcome was an adjusted hazard risk and 95% confidence interval (95% CI) of a 30% decrease in eGFR at month 36 from baseline.ResultsIn terms of eGFR, among participants treated with additional Kangxian Yanshen Formula, after adjusting for covariates, there was a 57.1% reduction in the risk of a 30% decline from baseline in eGFR among participants in the Kangxian Yanshen Formula group compared with the Western medicine group (adjusted hazard risk: 0.429; 95% CI 0.269–0.682). In addition, participants in the Kangxian Yanshen Formula group had a significantly higher change in eGFR from baseline to month 12 than those in the western medicine group (3.40 ± 11.62 versus −3.87 ± 8.39; between-group difference Δ5.61 [± 2.26 standard deviation] mL/min/1.73 m2; P = 0.014). Participants in both groups showed a decreasing trend in eGFR at months 24 and 36.ConclusionIn patients with stage 3–4 CKD, Kangxian Yanshen Formula Chinese medicine therapy may help delay eGFR decline, but high-quality randomized controlled trials are needed to validate the results further.

Abstract Objective The molecular mechanism of the protective effect of Cordyceps cicadae polysaccharides (CCPs) on renal tubulointerstitial fibrosis in diabetic nephropathy (DN) is still unclear. This study aims to further understand the molecular mechanisms behind the therapeutic benefits of CCP on diabetic nephropathy. Methods Mice were randomly assigned into six groups (n = 8). Cordyceps cicadae polysaccharide dissolved in 5% dimethyl sulfoxide was administered by gavage for 12 consecutive weeks. The CCP doses were divided into low, medium, and high, 75, 150, and 300 mg/kg/day, respectively. The efficacy of CCP was determined by assessing the renal function and histological alterations in diabetic db/db mice. The degree of glomerular mesangial dilatation and sclerosis was evaluated using semiquantitative markers. Cell viability, apoptosis, epithelial–mesenchymal transition (EMT), inflammation, oxidative stress, and mitochondrial reactive oxygen species (ROS) in high glucose (HG)‐cultured MPC5 podocytes were determined. The interaction of miR‐30a‐3p and tripartite motif‐containing protein 16 (TRIM16) was examined by luciferase reporter assay. Western blotting, reverse transcription‐polymerase chain reaction, and immunofluorescence were used to analyze gene and protein expressions. Results The in vivo findings illustrated that CCP may protect mice with type 2 diabetes from inflammation and oxidative damage (P

Background Exercise research targeting chronic kidney disease (CKD) has been conducted for more than 30 years, and the benefits of exercise for CKD patients have been progressively demonstrated. This study analyzes citation classics on clinical intervention trials on exercise training and CKD to describe the research landscape and hotspots through bibliometric analysis.Methods To identify clinical trials of exercise training interventions for CKD with more than 100 citations from the Web of Science Core Collection database. Extracted bibliometric information, participant information, and study characteristics of the included articles. The total citations, annual average citations, publication of year, author keywords, and study-related data were bibliometric analyzed and described using Excel 2019 and VOSviewer software.Results A total of 30 citation classics were included, with a total citation frequency of 102 to 279 (mean ± standard deviation: 148.4 ± 49.4). The American Journal of Kidney Diseases (n = 7) published the most (n = 7) classic citations in the field of CKD exercise research, and the Journal of the American Society of Nephrology was the most cited. The hotspot of research around CKD and exercise training interventions focused on population (hemodialysis and end-stage renal disease), exercise type (resistance training, yoga, and leg-cycling), and outcomes (cardiovascular indices, physical performance, psychological status, kidney function, physical activity). Reported dropout rates ranged from 0.0% to 47.4%.Conclusion A bibliometric analysis of citation classics on exercise training and CKD highlights the potential benefits of exercise as a non-pharmacological therapy for patients with CKD, as well as developments and hotspots in the field.

Background Although handgrip strength is associated with all-cause mortality in patients with chronic kidney disease (CKD), whether this relationship is dose-related is unknown. Therefore, we examined dose-response relationships between handgrip strength and all-cause mortality in CKD patients based on previous studies by meta-analysis.Methods Data sources included three electronic databases (PubMed, Web of Science, and Embase) from inception through October 2023. The included cohort was a CKD population not limited to disease stage, and their handgrip strength was objectively measured. Two researchers independently screened studies, extracted data, and assessed the risk of bias. We utilized estimates of handgrip strength categories using robust-error meta-regression (REMR), pooled study-specific estimates, and established dose-response relationships. Outcomes of interest included only all-cause mortality.Results A total of 18 studies with 4810 participants (aged 47–71 years) were included. REMR modeling showed a U-shaped trend of association between handgrip strength and all-cause mortality in patients with CKD. Higher handgrip strength values, from 10 kg to approximately 28 kg, were associated with lower mortality risk. After that, the risk of death increased slightly.Conclusion A U-shaped association exists between handgrip strength and all-cause mortality risk in CKD patients. Future studies with quantitative measurements for each CKD stage will help to determine precise relative risk estimates between handgrip strength and mortality risk in patients with different stages of CKD.

Purpose: The number of clinical reports of acupuncture therapy in chronic kidney disease (CKD) is gradually increasing. This systematic review and meta-analysis aim to examine the therapeutic role of acupuncture therapy in kidney function and common symptoms in CKD patients.Methods: We searched Embase, PubMed, Scopus, Web of Science, China National Knowledge Infrastructure, WanFang, and WeiPu for randomized controlled trials comparing acupuncture treatment with control or placebo groups. We assessed the effect of acupuncture therapy in CKD patients using a meta-analysis with the hartung-knapp-sidik-jonkman random effects model. In addition, we visualized keyword co-occurrence overlay visualization with the help of VOSviewer software to describe the research hotspots of acupuncture therapy and CKD.Results: A total of 24 studies involving 1494 participants were included. Compared to the control group, acupuncture therapy reduced serum creatinine levels (standardized mean difference [SMD]: −0.57; 95% CI −1.05 to −0.09) and relieved pruritus (SMD: −2.20; 95% CI −3.84, −0.57) in patients with CKD, while the TSA showed that the included sample size did not exceed the required information size. The included studies did not report acupuncture-related adverse events.Conclusions: Acupuncture is an effective and safe treatment for improving kidney function and relieving pruritic symptoms in patients with CKD, but the very low evidence may limit this conclusion. The TSA suggests that high-quality trials are needed to validate the efficacy of acupuncture therapy.

Abstract Cholesterol 25‐hydroxylase (CH25H), an enzyme involved in cholesterol metabolism, regulates inflammatory responses and lipid metabolism. However, its role in kidney disease is not known. The author found that CH25H transcript is expressed mostly in glomerular and peritubular endothelial cells and that its expression increased in human and mouse diabetic kidneys. Global deletion of Ch25h in Leprdb/db mice aggravated diabetic kidney disease (DKD), which is associated with increased endothelial cell apoptosis. Treatment of 25‐hydroxycholesterol (25‐HC), the product of CH25H, alleviated kidney injury in Leprdb/db mice. Mechanistically, 25‐HC binds to GTP‐binding protein ADP‐ribosylation factor 4 (ARF4), an essential protein required for maintaining protein transport in the Golgi apparatus. Interestingly, ARF4's GTPase‐activating protein ASAP1 is also predominantly expressed in endothelial cells and its expression increased in DKD. Suppression of ARF4 activity by deleting ARF4 or overexpressing ASAP1 results in endothelial cell death. These results indicate that 25‐HC binds ARF4 to inhibit its interaction with ASAP1, and thereby resulting in enhanced ARF4 activity to confer renoprotection. Therefore, treatment of 25‐HC improves kidney injury in DKD in part by restoring ARF4 activity to maintain endothelial cell survival. This study provides a novel mechanism and a potential new therapy for DKD.

Abstract Background Physical inactivity is prevalent among individuals with chronic kidney disease (CKD) and is linked to unfavorable outcomes. In recent years, daily steps have emerged as a prominent target for interventions in clinical trials. The present study endeavors to scrutinize the effectiveness and/or efficacy of various interventions on daily steps in patients with full-spectrum CKD. Methods In December 2022, a systematic search was conducted across three databases, namely PubMed, Embase, and Web of Science, and subsequently updated in June 2023. The inclusion criteria included randomized controlled studies, quasi-experimental studies, and single-arm trials that assessed an intervention’s impact on objectively measured daily steps in patients with chronic kidney disease. The Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool was used to assess the risk of bias in non-randomized controlled trials (RCT), while the Cochrane revised tool (ROB-2) was utilized for RCTs. Results Seventeen studies were deemed eligible for inclusion in this review, with a focus on examining the efficacy and/or effectiveness of exercise training-based interventions (n = 10), daily step goal-oriented interventions (n = 4), mobile health (mHealth) interventions (n = 1), different dialysis modalities (n = 1), and a “Sit Less, Interact, Move More” intervention (n = 1). The studies exhibit variability in their characteristics and assessment tools, reflecting the findings’ heterogeneity. The results indicate that increasing physical activity levels remain challenging, as only a limited number of studies demonstrated significant improvements in participants’ daily step counts from baseline to endpoint. Conclusion Clinical trials with daily steps as an outcome are still lacking in the CKD population. Well-designed clinical trials that objectively assess the physical activity of CKD patients are needed.

Introduction Haemodialysis is the most common treatment option for patients with life-sustaining end-stage kidney disease (ESKD). In recent years, haemodiafiltration or haemofiltration has been widely used in patients with ESKD, and there are still conflicting findings as to whether both are superior to traditional haemodialysis. This systematic review and meta-analysis were designed to determine whether haemodiafiltration or haemofiltration is more effective than haemodialysis in reducing all-cause mortality risk in patients with ESKD.Methods and analysis We will perform a systematic PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library and Scopus search, including studies published before September 2023. Randomised controlled trials will be included exploring the effects of haemodiafiltration or haemofiltration compared with haemodialysis on prognosis in patients with ESKD. Outcomes of interest include all-cause mortality, cardiovascular events, dialysis adequacy and adverse effects. The Cochrane Collaboration tools (ROB-2) will assess the bias risk. Available data will be used to calculate effect sizes. Heterogeneity between studies will be evaluated with I2. The trial sequential analysis will be used to eliminate false-positive results. The certainty of the evidence will be assessed using Grading of Recommendations, Assessment, Development and Evaluation criteria.Ethics and dissemination This systematic review and meta-analysis was deemed exempt from ethics review. Results will be disseminated through publication in peer-reviewed journals and research conferences.PROSPERO registration number CRD42023464509.

Abstract Background Diabetic nephropathy (DN) is a chronic kidney disease that develops in patients with diabetes mellitus. Cordycepin (CRD), a secondary metabolite produced by Cordyceps militaris, has a variety of bioactive properties. In this study, DN mice and high glucose (HG)-treated HK-2 were used to evaluate the diagnostic value of CRD. Methods Quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence analysis, and immunohistochemical staining were used to assess changes in mRNA and protein expression. Oxidative stress was evaluated by detecting the production of reactive oxygen species (ROS) and the activity of antioxidant enzymes. Cell apoptosis was detected by the TUNEL and flow cytometric methods. The interaction of miR-193b-5p and myeloid leukemia 1 (MCL-1) was examined by bioinformatics analysis and luciferase reporter assay. The protective effects of CRD on DN mice were evaluated by examining DN related biochemical indicators and renal histopathology. Results In response to HG, the level of miR-193b-5p was elevated, whilst the level of MCL-1 was downregulated, and CRD therapy reversed this behavior. MCL-1 was further identified to be miR-193b-5p target. CRD attenuated HG-induced cell damage, inflammation and abnormal energy metabolism. Mechanistic investigations on in vitro models confirmed that protective effect of CRD against HG challenge to HK-2 cells is mediated through the regulation of expression of miR-193b-5p/MCL-1 axis. By examining DN related biochemical markers and renal histopathology, the protective effects of CRD on DN mice was assessed. Conclusions In summary, CRD decreased oxidative stress and inflammation by increasing miR-193b-5p and inactivating downstream MCL-1 in DN, hinting the pivotal values of CRD and miR-193b-5p in the management of DN.

Abstract Aims and Objectives The aim of this study was to assess the sleep quality in dialysis patients during the COVID‐19 epidemic and explore the association between negative psychology (including depression, anxiety, and stress) and sleep quality in this population. Design A cross‐sectional study including three centres. Methods (Patients or Public Contribution) This cross‐sectional study included 378 dialysis patients from April to May 2022 in three dialysis centres in Shanghai. Methods. Depression, anxiety, stress, and sleep quality were measured by the Hospital Anxiety and Depression Scale (HADS), Perceived Stress Scale‐14 (PSS‐14), and Pittsburgh sleep quality index (PSQI), respectively. With a threshold of 5 to classify participants into good and poor sleep quality, with HADS/PSS‐14 scores as independent variables (per standard deviation (SD) increment), respectively and binary Logistic regression model was constructed to explore the association between the three negative psychological aspects of depression, anxiety, and stress and sleep quality. Results The median PSQI score was 11.0 (mean ± SD: 11.8 ± 4.8). Among them, poor sleep quality (i.e., PSQI >5) was reported by 90.2% of participants. After adjusting for sociodemographic and disease‐related information, HADS‐depression was associated with a significant 49% (odds ratio (OR): 1.49; 95% CI 1.02–2.18) increase in the risk of poor sleep quality for each additional SD (2.4). Correspondingly, for each SD (7.1) increase in PSS‐14, the risk of poor sleep quality was significantly increased by 95% (OR: 1.95; 95% CI 1.35–2.82). Conclusion During the COVID‐19 pandemic, there was a significant negative association between negative psychology, such as depression and stress, and sleep quality in dialysis patients, and this relationship was independent of the dialysis modality. Relevance to Clinical Practice In the context of the rampant COVID‐19, the vast majority of dialysis‐dependent chronic kidney disease presents with severe sleep quality problems, and negative psychology is a potential influencing factor.

Elevated serum uric acid levels are an independent predictor of occurrence and development of chronic kidney disease (CKD) and are strongly associated with prognosis. Several clinical trials have demonstrated the benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. To evaluate and rank the effects and safety of various SGLT-2 for serum uric acid levels in patients with CKD. We performed a systematic PubMed, Embase, Scopus, and Web of Science search, including studies published before July 1, 2023. Two researchers independently extracted data on study characteristics and outcomes and assessed study quality using the Cochrane Collaboration’s risk of bias tool 2. The gemtc package of R software was used to perform network meta-analysis within a Bayesian framework. The primary outcome was serum uric acid levels, and the secondary outcome was adverse events. Effect sizes are reported as standardized mean differences (SMDs), risk ratio (RR), and 95% CI, respectively. The certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria. Eight RCTs (9367 participants) were included in this meta-analysis. The results of the paired meta-analysis showed that SGLT-2 inhibitors significantly reduced serum uric acid levels in patients with CKD compared with the placebo group (SMD −0.22; 95% CI −0.42 to –0.03; GRADE: low). Pooled analysis of any adverse events reported in the included studies showed similar incidence rates in the SGLT-2 inhibitor and placebo groups (RR: 0.99; 95% CI 0.97 to 1.00; p=0.147; GRADE: high). Subgroup analysis showed a statistically significant difference only for tofogliflozin. Further network meta-analysis showed that dapagliflozin 10 mg and ipragliflozin 50 mg may be the most effective in reducing uric acid levels. SGLT-2 inhibitors significantly reduced serum uric acid levels in patients with CKD, and dapagliflozin 10 mg and ipragliflozin 50 mg may be the optimal dosages. SGLT-2 inhibitors hold great promise as an antidiabetic therapeutic option for patients with CKD who have elevated serum uric acid levels. PROSPERO registration number: CRD42023456581.

Recent studies have shown that the combined use of renin angiotensin system inhibitor, SGLT2 inhibitors and/or mineralocorticoid receptor antagonist provides additional renal protection for patients with diabetic kidney disease (DKD). Similarly, in traditional Chinese medicine, the synergistic application of multiple herbs often brings more significant therapeutic effects. However, the synergistic or additive mechanisms of traditional Chinese medicine in combination therapy are not fully understood. In our previous studies, we show that arctigenin (ATG), a major component of Fructus Arctii, attenuates proteinuria and renal injury in diabetic mice by activating PP2A, and puerarin (a class of known isoflavones) can also reduce proteinuria and renal injury in diabetic mice via activation of Sirt1. Here, we further explored the potential additive renal protection of these two compounds in diabetic mice. Research has found that ATG and puerarin have a synergistic effect in reducing albuminuria in db/db mice. Mechanistically, we found that ATG reduced NF-κB p65 phosphorylation likely through activation of PP2A while puerarin reduced p65 acetylation via Sirt1 activation. Therefore, ATG and puerarin have additive inhibitory effects on the NF-κB activation, which is a key inflammatory pathway in DKD. RNA-sequencing analysis revealed distinct pathways activated by ATG and puerarin in the diabetic kidney, which may provide an additional mechanism for their additive effects in DKD. Our study suggests that ATG and puerarin could be a new combination therapy for DKD and reveals its underlined mechanisms.

Renal interstitial fibrosis (RIF), a progressive process affecting the kidneys in chronic kidney disease (CKD), currently lacks an effective therapeutic intervention. Traditional Chinese medicine (TCM) has shown promise in reducing RIF and slowing CKD progression. In this study, we demonstrated the dose-dependent attenuation of RIF by Ootheca mantidis (SPX), a commonly prescribed TCM for CKD, in a mouse model of unilateral ureteral obstruction (UUO). RNA-sequencing analysis suggested that SPX treatment prominently downregulated apoptosis and inflammation-associated pathways, thereby inhibiting the fibrogenic signaling in the kidney. We further found that transplantation of fecal microbiota from SPX-treated mice conferred protection against renal injury and fibrosis through suppressing apoptosis in UUO mice, indicating that SPX ameliorated RIF via remodeling the gut microbiota and reducing apoptosis in the kidneys. Further functional exploration of the gut microbiota combined with fecal metabolomics revealed increased levels of some probiotics, including Akkermansia muciniphila (A. muciniphila), and modulations in glutamine-related amino acid metabolism in UUO mice treated with SPX. Subsequent colonization of A. muciniphila and supplementation with glutamine effectively mitigated cell apoptosis and RIF in UUO mice. Collectively, these findings unveil a functionally A. muciniphila- and glutamine-involved gut–renal axis that contributes to the action of SPX, and provide important clue for the therapeutic potential of SPX, A. muciniphila, and glutamine in combatting RIF.

For a long time, fish school swimming has attracted a great deal of attention in biological systems, as fish schools can have complex hydrodynamic effects on individuals. This work adopted a non-iterative, immersed boundary–lattice Boltzmann method (IB–LBM). A numerical simulation of two-dimensional three-degree-of-freedom self-propelled fish, in side-by-side, staggered, and triangle formations, was conducted by adjusting spacing and motion parameters. A comprehensive analysis of individual speed gains and energy efficiencies in these formations was carried out. Furthermore, an analysis of the hydrodynamic characteristics of fish schools was performed, using instantaneous vorticity profiles and pressure fields. Certain studies have shown that passive interactions between individuals cannot always bring hydrodynamic benefits. The swimming efficiency of side-by-side formations in the same phase gradually increases as the distance decreases, but it also brings certain burdens to individuals when the phases are different. This paper also shows that the roles of passive interactions, spacing, and deflections affect fish school subsystems differently. When the low-pressure areas created by a wake vortex act on one side of an individual’s body, the tail-end fish are good at gaining hydrodynamic benefits from it. This effect is not universal, and the degree to which individuals benefit from changes in exercise parameters varies. This study provides a theoretical basis for bioinspired robots, as well as providing certain insights into the mechanism of collective biological movement.

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Increasing evidence has suggested that inflammation is a key microenvironment involved in the development and progression of DN. Studies have confirmed that macrophage accumulation is closely related to the progression to human DN. Macrophage phenotype is highly regulated by the surrounding microenvironment in the diabetic kidneys. M1 and M2 macrophages represent distinct and sometimes coexisting functional phenotypes of the same population, with their roles implicated in pathological changes, such as in inflammation and fibrosis associated with the stage of DN. Recent findings from single-cell RNA sequencing of macrophages in DN further confirmed the heterogeneity and plasticity of the macrophages. In addition, intrinsic renal cells interact with macrophages directly or through changes in the tissue microenvironment. Macrophage depletion, modification of its polarization, and autophagy could be potential new therapies for DN.

The incidence and prevalence of chronic kidney disease (CKD) continue to increase worldwide remaining as a major public health burden. CKD eventually progresses to end-stage kidney failure and patients with CKD have high morbidity and mortality. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylases, has significant renal protective effects through its regulation of fibrosis, apoptosis, and senescence, oxidative stress, inflammation and aging process. The renal protective effects of Sirt1 have been described in many kidney diseases such as diabetic kidney disease and HIV-related kidney disease. SIRT1 also has protective effects against vascular calcification and therefore could be developed as a therapy for both CKD and CKD complications. In this narrative review, we will give an overview of the recent progress on the role of SIRT1 and its downstream pathways in CKD. We will also discuss potential therapeutic approach by activating SIRT1-related pathway in patients with CKD. The purpose is to hope to provide some insights on the future direction of the research in the field of SIRT1 for CKD.

Arctigenin (ATG) is the major active component of a Chinese herbal remedy known to reduce proteinuria in patients with diabetic kidney disease (DKD). Here, Zhong et al. identify PP2A as a pharmacological target of ATG in podocytes, and find that PP2A is responsible for some of the beneficial effects of ATG in mouse models of DKD.

Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.

Tactile sensation is a highly desired function in robotics. Furthermore, tactile sensor arrays are crucial sensing elements in pulse diagnosis instruments. This paper presents the fabrication of an integrated piezoresistive normal force sensor through surface micromachining. The force sensor is transferred to a readout circuit chip via a temporary stiction effect handling process. The readout circuit chip comprises two complementary metal-oxide semiconductor operational amplifiers, which are redistributed to form an instrumentation amplifier. The sensor is released and temporarily bonded to the substrate before the transfer process due to the stiction effect to avoid the damage and movement of the diaphragm during subsequent flip-chip bonding. The released sensor is pulled off from the substrate and transferred to the readout circuit chip after being bonded to the readout circuit chip. The size of the transferred normal force sensor is 180 μm × 180 μm × 1.2 μm. The maximum misalignment of the flip-chip bonding process is approximately 1.5 μm, and sensitivity is 93.5 μV/μN/V. The routing of the piezoresistive Wheatstone bridge can be modified to develop shear force sensors; consequently, this technique can be used to develop tactile sensors that can sense both normal and shear forces.

Puerarin, an active compound of radix puerariae, is a major compound used in Chinese herbal medicines to treat patients with diabetic nephropathy (DN). In the previous studies, we showed that puerarin exerts renoprotective effects in Streptozocin (STZ)-induced diabetic mice through activation of Sirt1 and anti-oxidative effects. Here, we further investigated the underlying mechanism mediating the renal protective effects of puerarin in DN. We studied the effects and mechanism of puerarin in STZ-induced diabetic mice and in cultured immortalized mouse podocytes treated with high glucose. We confirmed that puerarin ameliorated urinary albumin creatinine ratio and kidney injury in STZ-induced DN mice. We found that expression of heme oxygenase 1 (HMOX-1) and Sirt1 was suppressed in diabetic glomeruli but restored by puerarin treatment at both mRNA and protein levels. Additionally, we found that puerarin induced autophagy in the kidney of DN mice. In conditionally immortalized mouse podocytes, puerarin inhibited HG-induced apoptosis and restored the mRNA and protein levels of HMOX-1 and Sirt1. Interestingly, we showed that puerarin decreased liver kinase B1 (LKB1) acetylation, thereby promoting adenosine 5′-monophosphate-activated protein kinase-dependent autophagy. Knockdown of HMOX-1 and Sirt1 expression or treatment with the autophagy inhibitor 3-methyladenine abolished the protective effects of puerarin in HG-treated podocytes. Taken together, these results suggest that puerarin protects podocytes from diabetes-induced injury through HMOX1 and Sirt1-mediated upregulation of autophagy, a novel mechanism explaining its renal protective effects in DN.

Diabetic kidney disease (DKD) is the most common microvascular complication of diabetes and is one of the main causes of end-stage renal disease (ESRD) in many countries. The pathological features of DKD are the hypertrophy of mesangial cells, apoptosis of podocytes, glomerular basement membrane (GBM) thickening, accumulation of extracellular matrix (ECM), glomerular sclerosis, and tubulointerstitial fibrosis. The etiology of DKD is very complicated and many factors are involved, such as genetic factors, hyperglycemia, hypertension, hyperlipidemia, abnormalities of renal hemodynamics, and metabolism of vasoactive substances. Although some achievements have been made in the exploration of the pathogenesis of DKD, the currently available clinical treatment methods are still not completely effective in preventing the progress of DKD to ESRD. CHM composed of natural products has traditionally been used for symptom relief, which may offer new insights into therapeutic development of DKD. We will summarize the progress of Chinese herbal medicine (CHM) in the treatment of DKD from two aspects. In clinical trials, the Chinese herbal formulas were efficacy and safety confirmed by the randomized controlled trials. In terms of experimental research, studies provided evidence for the efficacy of CHM from the perspectives of balancing metabolic disorders, reducing inflammatory response and oxidative stress, antifibrosis, protecting renal innate cells, and regulating microRNA and metabolism. CHM consisting of different ingredients may play a role in synergistic interactions and multiple target points in the treatment of DKD.

In this study, we developed a radial artery pulse acquisition system based on finger-worn dense pressure sensor arrays to enable three-dimensional pulse signals acquisition. The finger-worn dense pressure-sensor arrays were fabricated by packaging 18 ultra-small MEMS pressure sensors (0.4 mm × 0.4 mm × 0.2 mm each) with a pitch of 0.65 mm on flexible printed circuit boards. Pulse signals are measured and recorded simultaneously when traditional Chinese medicine practitioners wear the arrays on the fingers while palpating the radial pulse. Given that the pitches are much smaller than the diameter of the human radial artery, three-dimensional pulse envelope images can be measured with the system, as can the width and the dynamic width of the pulse signals. Furthermore, the array has an effective span of 11.6 mm—3–5 times the diameter of the radial artery—which enables easy and accurate positioning of the sensor array on the radial artery. This study also outlines proposed methods for measuring the pulse width and dynamic pulse width. The dynamic pulse widths of three volunteers were measured, and the dynamic pulse width measurements were consistent with those obtained by color Doppler ultrasound. The pulse wave velocity can also be measured with the system by measuring the pulse transit time between the pulse signals at the brachial and radial arteries using the finger-worn sensor arrays.

Multiple studies have demonstrated a critical role of Sirtuin-1 (SIRT1) deacetylase in protecting kidney cells from cellular stresses. A protective role of SIRT1 has been reported in both podocytes and renal tubular cells in multiple kidney disease settings, including diabetic kidney disease (DKD). We and others have shown that SIRT1 exerts renoprotective effects in DKD in part through the deacetylation of transcription factors involved in the disease pathogenesis, such as p53, FOXO, RelA/p65NF-κB, STAT3, and PGC1α/PPARγ. Recently we showed that the podocyte-specific overexpression of SIRT1 attenuated proteinuria and kidney injury in an experimental model of DKD, further confirming SIRT1 as a potential target to treat kidney disease. Known agonists of SIRT1 such as resveratrol diminished diabetic kidney injury in several animal models. Similarly, we also showed that puerarin, a Chinese herbal medicine compound, activates SIRT1 to provide renoprotection in mouse models of DKD. However, as these are non-specific SIRT1 agonists, we recently developed a more specific and potent SIRT1 agonist (BF175) that significantly attenuated diabetic kidney injury in type 1 diabetic OVE26 mice. We also previously reported that MS417, a bromodomain inhibitor that disrupts the interaction between the acetyl-residues of NF-κB and bromodomain-containing protein 4 (BRD4) also attenuates DKD. These results suggest that SIRT1 agonists and bromodomain inhibitors could be potential new therapuetic treatments against DKD progression.

Renal interstitial fibrosis is characterized by inflammation and an excessive accumulation of extracellular matrix, which leads to end-stage renal failure. Our previous studies have shown that a natural product from Cordyceps cicadae can ameliorate chronic kidney diseases. N6-(2-Hydroxyethyl) adenosine (HEA), a physiologically active compound in C. cicadae, has been identified as a Ca2+ antagonist and an anti-inflammatory agent in pharmacological tests. However, its role in renal interstitial fibrosis and the underlying mechanism remains unclear. Here, unilateral ureteral obstruction (UUO) was used to induce renal interstitial fibrosis in male C57BL/6 mice. Different doses of HEA (2.5, 5, and 7.5 mg/kg) were given by intraperitoneal injection 24 h before UUO, and the treatment was continued for 14 days post-operatively. Histologic changes were examined by hematoxylin & eosin, Masson’s trichrome, and picrosirius red stain. Quantitative real-time PCR analysis, enzyme-linked immunosorbent assays, immunohistochemistry, and western blot analysis were used to evaluate proteins levels. And the results showed that HEA significantly decreased UUO-induced renal tubular injury and fibrosis. In vivo, HEA apparently decreased UUO-induced inflammation and renal fibroblast activation by suppression of the NF-κB and TGF-β1/Smad signaling pathway. In vitro, HEA also obviously decreased lipopolysaccharide-induced inflammatory cytokine level in RAW 264.7 cells and TGF-β1-induced fibroblast activation in NRK-49F cells by modulating NF-κB and TGF-β1/Smad signaling. In general, our findings indicate that HEA has a beneficial effect on UUO-induced tubulointerstitial fibrosis by suppression of inflammatory and renal fibroblast activation, which may be a potential therapy in chronic conditions such as renal interstitial fibrosis.

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Renal relapse is a very common manifestation of IgA nephropathy (IgAN). The clinical characteristics and long-term outcomes of this condition have not yet been carefully explored.Patients with biopsy-proven IgAN between January 2005 and December 2010 from three medical centers in China was a primary cohort of patients. From January 2010 to April 2012, data of an independent cohort of IgAN patients from Ren Ji Hospital, Shanghai, China was collected using the same inclusion and exclusion criteria. These patients formed the validation cohort of this study.Of the patients with biopsy-proven IgAN from three medical centers, 489 patients achieved remission within 6 months following the therapy. Additionally, 76 (15.5%) of these patients experienced a relapse after achieving remission. During the median follow-up period of 66 months, 6 patients (1.4%) in the non-relapse group experienced renal deterioration, compared with 22 patients (29.6%) in the relapse group. Our study indicated that each 1-mmHg increase in the baseline diastolic blood pressure (DBP) was associated with a 4.5% increase in the risk of renal relapse; additionally, the male patients had a 3.324-fold greater risk of relapse compared with the female patients according to the adjusted multivariate Cox analysis. The nomogram was based on 489 patients achieved remission. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling on the validation cohort.This study demonstrated that renal relapse is a potential predictor of prognostic outcomes in patients under the current therapeutic regimens for IgAN. And male patients with higher diastolic blood pressure had a greater risk of experiencing relapse.

Nephrokeli (NPKL) is a Chinese herbal formula that has been used to treat patients with IgA nephropathy (IgAN) for improvement of proteinuria and kidney injury. However, the mechanism remains unclear. Sphingosine-1-phosphate (S1P) and its receptors S1PR2 and S1PR3 are known to play an important role in kidney disease. Here, we tested whether NPKL is able to regulate the S1P pathway in the kidney of IgAN rats. Four groups of rats were included in the study: Control, IgAN, IgAN treated with losartan, and IgAN treated with NPKL. The IgAN model was generated by injection of bovine serum albumin and staphylococcus enterotoxin B. We found that IgAN rats had increased staining for proliferating cell nuclear antigen (PCNA) in the mesangial area and increased mRNA and protein levels of S1PR2 and S1PR3 in the kidney compared to control rats. Connective tissue growth factor (CTGF), a downstream growth factor in the S1P pathway, was also elevated in the kidney of IgAN rats. Treatment with either NPKL or losartan was able to reduce PCNA staining and the expression of both S1PR2 and S1PR3 in the kidney of IgAN rats. However, NPKL (but not losartan treatment) reduced the expression of CTGF in the kidney of IgAN rats. In addition, we treated rat mesangial cells with sera collected from either NPKL-treated rats or control rats and found that NPKL-serum was able to reduce S1P-induced mesangial cell proliferation and the expression of S1PR2/S1PR3 and CTGF. NPKL also attenuates expression of fibrosis, inflammation, and oxidative stress markers in the kidney of IgAN rats. Our studies provide the mechanism by which NPKL attenuates kidney injury in IgAN rats.

Radix puerariae, a traditional Chinese herbal medication, has been used successfully to treat patients with early stage of diabetic nephropathy. However, the underlined mechanism of this renal protective effect has not been determined. In the current study, we investigated the effects and the mechanism of puerarin in Streptozotocin (STZ)-induced diabetic rats. We treated STZ-rats with either puerarin or losartan, an angiotensin II receptor blocker, as compared to those treated with vehicle. We found that both puerarin and losartan attenuated kidney hypertrophy, mesangial expansion, proteinuria, and podocyte foot process effacement in STZ rats. In addition, both puerarin and losartan increased expression of podocyte slit diaphragm proteins such as nephrin and podocin. Interestingly, we found that puerarin treatment induced a more pronounced suppression of oxidative stress production and S-nitrosylation of proteins in the diabetic kidneys as compared to losartan treatment. Furthermore, we found that matrix metalloproteinase-9 (MMP-9), which is known to be activated by oxidative stress and S-nitrosylation of proteins, was also suppressed more extensively by puerarin than losartan. In conclusion, these data provide for the first time the potential mechanism to support the use of puerarin in the treatment of early diabetic nephropathy.

Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.