Serum Vitamin D: Correlates of Baseline Concentration and Response to Supplementation in VITAL-DKD.

CONTEXT: The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. OBJECTIVE: To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials. DESIGN: Exploratory study within a randomized trial. INTERVENTION: 2000 International Units of vitamin D3 per day (or matching placebo). SETTING: Community-based. PARTICIPANTS: 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. MAIN OUTCOME MEASURES: Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. RESULTS: At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05). CONCLUSIONS: Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.

Can Probiotics Supplementation Improve Glycemic and Renal Status in Diabetic Nephropathy? A Systematic Review and Meta-Analysis of Clinical Trials.

BACKGROUND & AIM: This meta-analysis was performed to quantify the effects of probiotics on renal and glycemic biomarkers among patients with Diabetic Nephropathy (DN). METHODS: Electronic databases were searched on May 10, 2020. All trials that investigated the effect of probiotics on serum glycemic markers (Fasting Plasma Glucose [FPG], Hemoglobin A1C, Insulin, Homeostatic Model Assessment-Insulin Resistance [HOMA-IR], and Quantitative Insulin Sensitivity Check Index [QUICKI]), and renal status markers (Creatinine [Cr], Blood Urea Nitrogen [BUN], and Glomerular Filtration Rate [GFR]) were included. RESULTS: Seven trials that included 340 patients were identified for analysis. The results indicated that probiotics significantly reduced FPG (WMD= -19.08 mg/dl; 95% CI= -32.16, -5.99; P=0.004), HOMA-IR (WMD= -1.88; 95% CI= -3.63, -0.12; P=0.036), and Cr (WMD= -0.18 mg/dl; 95% CI= -0.26, -0.09; P<0.001) levels in DN patients; however, there was no statistically significant change in Hemoglobin A1C, Insulin, QUICKI, BUN, and GFR. CONCLUSION: This meta-analysis supports the potential use of probiotics in the improvement of some glycemic and renal biomarkers in patients with DN.

Efficacy and safety of astragalus injection combined with Western medicine in the treatment of early diabetic nephropathy: A protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes. Its clinical manifestation is proteinuria, and it is a common cause of renal failure. At present, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists are often used to treat early DN, and they have good curative effect. On this basis, the treatment of early DN with the combination of astragalus injection is becoming more and more widespread. Therefore, the purpose of this study is to prove the efficacy and safety of astragalus injection combined with Western medicine in the treatment of early DN, and to provide reference value for clinical practice in the future. METHODS: English databases (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese databases (China National Knowledge Infrastructur, Wanfang, VP Information Chinese Journal Service Platform, China Biology Medicine disc) will be searched by computer. From the establishment of the database to February 2021, a randomized controlled trial of astragalus injection combined with Western medicine in the treatment of early DN will be conducted. Two researchers independently evaluate the quality of the included study and extract the data. Included literature is analyzed by Meta with RevMan5.3 software. RESULTS: In this study, the efficacy and safety of astragalus injection combined with Western medicine in the treatment of early DN are evaluated by serological indexes such as Urinary albumin excretion rates (UAER), serum creatinine and blood urea nitrogen, as well as the adverse reactions of drugs. CONCLUSION: This study will provide reliable evidence-based evidence for astragalus injection combined with Western medicine for the treatment of early DN. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/A9JGP.

Dietary Phosphorus as a Marker of Mineral Metabolism and Progression of Diabetic Kidney Disease.

Phosphorus is an essential nutrient that is critically important in the control of cell and tissue function and body homeostasis. Phosphorus excess may result in severe adverse medical consequences. The most apparent is an impact on cardiovascular (CV) disease, mainly through the ability of phosphate to change the phenotype of vascular smooth muscle cells and its contribution to pathologic vascular, valvular and other soft tissue calcification. Chronic kidney disease (CKD) is the most prevalent chronic disease manifesting with the persistent derangement of phosphate homeostasis. Diabetes and resulting diabetic kidney disease (DKD) remain the leading causes of CKD and end-stage kidney disease (ESRD) worldwide. Mineral and bone disorders of CKD (CKD-MBD), profound derangement of mineral metabolism, develop in the course of the disease and adversely impact on bone health and the CV system. In this review we aimed to discuss the data concerning CKD-MBD in patients with diabetes and to analyze the possible link between hyperphosphatemia, certain biomarkers of CKD-MBD and high dietary phosphate intake on prognosis in patients with diabetes and DKD. We also attempted to clarify if hyperphosphatemia and high phosphorus intake may impact the onset and progression of DKD. Careful analysis of the available literature brings us to the conclusion that, as for today, no clear recommendations based on the firm clinical data can be provided in terms of phosphorus intake aiming to prevent the incidence or progression of diabetic kidney disease.

Network pharmacology combined with metabolomics to study the mechanism of Shenyan Kangfu Tablets in the treatment of diabetic nephropathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenyan Kangfu Tablets (SYKFT) is a traditional prescription evolved from Shenqi Pills. It has been included in the Synopsis of the Golden Chamber for more than 2000 years. SYKFT was listed as a national Chinese medicine protected class by the China Food and Drug Administration. Diabetic nephropathy (DN) is one of the serious microvascular diseases caused by diabetes and is also one of the important factors leading to the death of patients. The pathogenesis of DN is diverse and complex, and there is no particularly effective drug treatment. There is clinical evidence that SYKFT has a good therapeutic effect on DN with no obvious adverse effects, but the mechanism of treatment is not clear. AIM OF THE STUDY: In this study, network pharmacology was combined with metabolomics technology to explore the mechanism of SYKFT in the treatment of DN. MATERIALS AND METHODS: First, the research team conducted a qualitative study of the chemical components contained in SYKFT, and carried out network pharmacology to search for potential targets based on the characterized chemical components. Second, we analysed the metabolic profile of db/db mouse urine based on UHPLC-QTOF-MS technology, and biomarkers were identified by multivariate statistical analysis. Then, we performed further pathway enrichment analysis. Finally, the results of metabolomics and network pharmacology were conjointly analysed. RESULTS: Seventy-five chemical components of SYKFT were identified. According to the TCMSP database, the corresponding targets of the qualitatively identified components were searched, and a total of 36 potentially active components and 160 targets related to DN were obtained. A total of 38 biomarkers were found in metabolomics based on UHPLC-QTOF-MS technology. Biosynthesis of unsaturated fatty acids and starch and sucrose metabolism are the most related pathways, the former of which has been rarely reported concerning DN. Finally, the results of the joint analysis show that two targets, hexokinase 2 (HK2) and maltase glucoamylase (MGAM), are the overlapping targets. It means they are not only the related targets of pathways involved in potential biomarkers in metabolomics but also the intersection targets of diseases and drugs identified by network pharmacology. CONCLUSIONS: The study reveals that the potential mechanism of SYKFT is most related to insulin resistance (IR) in the treatment of DN. It also proves that network pharmacology combined with metabolomics to find the mechanisms by which herbs treat complex diseases is a feasible tool.

Tiliacora triandra extract and its major constituent attenuates diabetic kidney and testicular impairment by modulating redox imbalance and pro-inflammatory responses in rats.

BACKGROUND: Literature has demonstrated that diabetes is associated with renal complication and testicular dysfunctions. The current study explored the potential of Tiliacora triandra extract and its major component against diabetic kidney and testicular damages in rats. METHODS: Diabetes was induced by high fat diet/streptozotocin (HFD/STZ) and treated orally with Tiliacora triandra extract (TTE, 100 and 400 mg kg-1 body weight) and its major component, 5,7-dihydroxy-6-oxoheptadecanoic acid (DHA, 25 mg kg-1 body weight) for 30 consecutive days. Testicular activities of testicular enzymes, serum levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), sperm parameters and urinalysis for protein and albumin levels were evaluated. Renal and testicular biomarkers of oxidative stress and pro-inflammation were analysed along with histology. RESULTS: The experimental diabetes induced significant alterations in the levels and activities of indices evaluated compared to non-diabetic normal rats. The 28-day treatment of diabetic rats with TTE and DHA markedly improved activities of testicular enzymes, restored levels of testosterone, LH and FSH and sperm parameters compared to untreated diabetic rats. TTE and DHA abrogated proteinuria and reversed urine albumin level. Testicular and renal oxidative stress and pro-inflammation were attenuated in diabetic rats treated with TTE and DHA. The diabetes-mediated histopathological damage was alleviated in the kidney and testis. CONCLUSION: The protective effect of TTE and DHA against diabetes induced kidney and testicular damages may be related to its antioxidant and anti-inflammatory activities. © 2020 Society of Chemical Industry.

QiDiTangShen granules modulated the gut microbiome composition and improved bile acid profiles in a mouse model of diabetic nephropathy.

QiDiTangShen granules (QDTS), a traditional Chinese herbal medicine, have been used in clinical practice for treating diabetic kidney disease for several years. In our previous study, we have demonstrated that QDTS displayed good efficacy on reducing proteinuria in mice with diabetic nephropathy (DN). However, the exact mechanism by which QDTS exerts its reno-protection remains largely unknown. To ascertain whether QDTS could target the gut microbiota-bile acid axis, the db/db mice were adopted as a mouse model of DN. After a 12-week of treatment, we found that QDTS significantly reduced urinary albumin excretion (UAE), and attenuated the pathological injuries of kidney in the db/db mice, while the body weight and blood glucose levels of those mice were not affected. In addition, we found that QDTS significantly altered the gut microbiota composition, and decreased serum levels of total bile acid (TBA) and BA profiles such as ß-muricholic acid (ß-MCA), taurocholic acid (TCA), tauro ß-muricholic acid (Tß-MCA) and deoxycholic acid (DCA). These BAs are associated with the activation of farnesoid X receptor (FXR), which is highly expressed in kidney. However, there was no significant difference between QDTS-treated and -untreated db/db mice regarding the renal expression of FXR, indicating that other mechanisms may be involved. Conclusively, our study revealed that QDTS significantly alleviated renal injuries in mice with DN. The gut microbiota-bile acid axis may be an important target for the reno-protection of QDTS in DN, but the specific mechanism merits further study.

Association Between Vitamin D Status and Diabetic Complications in Patients With Type 2 Diabetes Mellitus: A Cross-Sectional Study in Hunan China.

Background: Vitamin D status has been linked to diabetes-related complications due to multiple extraskeletal effects. We aimed to investigate the association between vitamin D deficiency (VDD) and diabetic vascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic foot ulcers (DFU). Methods: A total of 4,284 Chinese patients with type 2 diabetic mellitus (T2DM) were enrolled into the cross-sectional study. VDD was defined as serum 25-hydroxyvitamin D <50 nmol/L. Demographic data, physical measurements, laboratory measurements, comorbidities, and related medications were collected and analyzed by VDD status. Poisson regression with robust variance estimation and binary logistic regression were performed to explore the relationship between VDD and diabetic complications. Results: The prevalence of VDD, DR, DKD, DFU accounted to 71.7% (95% confidence intervals [CI]: 70.3-73.0%), 28.5% (95% CI: 27.2-29.9%), 28.2% (95% CI: 26.8-29.5%), and 5.7% (95% CI: 5.1-6.5%), respectively. The prevalence ratios (95% CI) for DR and DKD by VDD status, adjusted for demographics, physical measurements, laboratory measurements, related complications, and comorbidities, and medications, were 1.093 (0.983-1.215) and 1.041 (0.937-1.156), respectively. The odds ratio (95% CI) for DFU by VDD status was 1.656 (1.159-2.367) in the final adjusted model. Meanwhile, the prevalence of VDD was significantly higher in patients with DFU compared with patients without DFU. Conclusions: The present study firstly indicated that VDD was significantly associated with a higher prevalence of DFU among Chinese T2DM patients. The association between VDD status and DR or DKD was not significant when adjusting for all potential covariates. Vitamin D screening or supplementation may be beneficial to prevent DFU and improve the prognosis of T2DM patients.

A randomized controlled clinical trial study protocol of Liuwei Dihuang pills in the adjuvant treatment of diabetic kidney disease.

INTRODUCTION: A large number of patients with diabetic kidney disease (DKD) approach traditional Chinese medicine (TCM) owing to discontent with standard treatments. Based on TCM theory and clinical experience, the syndrome of kidney yin deficiency is a common type of DKD. Liuwei Dihuang pills (LDPs) is a common prescription of a Chinese herbal formula for patients presenting this syndrome of DKD. However, well-established data supporting the efficacy and safety of LDP in DKD treatment are lacking. METHODS: We have designed a double-blind, placebo-controlled, randomized trial. After a 2-week run-in period, 124 eligible participants with DKD will be assigned to either the experimental or the control group in a 1:1 ratio. Patients in the experimental group will receive LDP, while patients in the control group will receive a matched placebo. As the basic treatment in the 2 groups, metformin hydrochloride sustained-release tablets, for blood glucose control, and irbesartan tablets, for blood pressure regulation, will be provided. All participants will undergo 4 weeks of treatment and 12 weeks of follow-up. The primary outcome is the change in 24 hours urinary protein levels, measured from the baseline to the end of the treatment phase (week 24). The secondary outcomes to be assessed include the change in serum creatinine and estimated glomerular filtration rate, urinary albumin excretion rate, improvement of TCM syndromes and symptoms, fasting blood glucose and postprandial 2-hour blood glucose, blood lipids (total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, from baseline to weeks 12 and 24. DISCUSSION: The results of this study will provide high-quality evidence of the effects of LDP in DKD treatment, which will provide an alternative treatment strategy in patients with DKD.

Triphala Ameliorates Nephropathy via Inhibition of TGF-ß1 and Oxidative Stress in Diabetic Rats.

INTRODUCTION: Advanced glycation end products, oxidative stress, and TGF-ß expression play a crucial role in pathophysiology of diabetic nephropathy. Inhibition of oxidative stress and TGF-ß expression by natural traditional medicines may give an economic and safe alternative treatment option. Triphala churna, a traditional medicine, has been proved to have potent antioxidant activity, and individual components of it have shown significant antidiabetic activity. Hence, the present study was designed to study the effect of Triphala churna in diabetic nephropathy in rats. METHODS: Diabetes was induced in rats by administration of streptozotocin (55 mg/kg i.p.). Four weeks after induction of diabetes, the animals were treated with Triphala churna at the doses of 250, 500, and 1,000 mg/kg for next 4 weeks. Various biochemical and urine parameters such as glucose, creatinine, blood urea nitrogen (BUN), total protein, and albumin were assessed at the end of study. Creatinine clearance, BUN clearance, and glomerular filtration rate were determined. Oxidative stress parameters such as malondialdehyde, catalase, reduced glutathione, and superoxide dismutase were determined in kidney tissues. TGF-ß1 expression was measured with ELISA, immunohistochemistry, and western blot techniques. Histopathology study was carried out with haemotoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining to determine histological changes. RESULTS: Treatment with Triphala churna significantly improved urine parameters. Triphala churna treatment also improved plasma proteins, albumin, creatinine, and BUN levels. The oxidative stress was reduced in the kidney with the treatment of Triphala churna. Histopathological studies revealed that Triphala churna reduced kidney damage. Immunohistochemistry, ELISA, and western blotting study revealed that treatment with Triphala decreased the expression of TGF-ß in kidney tissues. CONCLUSION: From the results, it can be concluded that Triphala churna has a significant nephroprotective effect because of its capability of inhibiting oxidative stress and TGF-ß in diabetes.

Astragalus polysaccharides protect renal function and affect the TGF-ß/Smad signaling pathway in streptozotocin-induced diabetic rats.

OBJECTIVES: The objective was to observe the effects of Astragalus polysaccharides on diabetes and on regulation of the TGF-ß/Smad signaling pathway. METHODS: A type 2 diabetic rat model was established with a high-fat diet in combination with low-dose streptozotocin (35 mg/kg). Astragalus polysaccharides were applied as treatment intervention and changes in blood glucose and kidney morphology and function were assessed. RESULTS: Eight weeks after model establishment, kidney weight as a proportion of total weight (KW/TW) in the high-, medium-, and low-dose Astragalus polysaccharide groups was significantly lower than that in the model group, and the KW/TW value gradually decreased with increasing dose of polysaccharides in each treatment group. Fasting blood glucose in the low- and medium-dose Astragalus polysaccharide groups was numerically lower than that in the model group and fasting blood glucose in rats in the high-dose group was significantly lower than that in the model group. Levels of 24-hour urinary microalbumin, creatinine, blood urea nitrogen, collagens I, III, and IV, α-smooth muscle actin, transforming growth factor-ß1, and Smad3 in Astragalus polysaccharide groups (all doses) were significantly lower than those in the model group. CONCLUSIONS: Astragalus polysaccharide significantly improved blood glucose and protected kidney function in a rat diabetes model.

Therapeutic effect of Chinese prescription Kangen-karyu in patients with diabetic nephropathy.

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. A number of new therapies have been developed based on the pathogenic factors of diabetic nephropathy such as intensive glycemic control, precise hypertension control, lifestyle modifications including exercise and an energy-restricted diet, and numerous novel agents. The utilization of traditional Chinese medicine for patients with diabetic nephropathy has also received increasing attention due to its wide availability, weak side-effects, and proven therapeutic mechanisms and benefits. In this paper, we report the case of patients with diabetic nephropathy, stage 2 or 3. Kangen-karyu extract (7.5 g/day) was administered three times per day for 6 months. The estimated glomerular filtration rate was increased at the 6-month follow-up. The serum creatinine level decreased following administration. At that time, somatic and subjective symptoms had partially disappeared. Here, we present evidence that Kangen-karyu exerts a renoprotective effect against the development of diabetic nephropathy.

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice.

Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta-Ins2Akita (KK-Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l-aspartic acid) levels in diabetic KK-Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK-Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK-Akita mice (DKD group), and (c) treated (double-volume Asp diet) KK-Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate-labeled lectins, wheat germ agglutinin (WGA), and anti-endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.

Korean red ginseng attenuates hyperglycemia-induced renal inflammation and fibrosis via accelerated autophagy and protects against diabetic kidney disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C.A. Mey. (Korean ginseng) has been widely used in traditional medicine to treat diabetes mellitus for thousands of years. It also plays a key role in health maintenance owing to its anti-oxidant and anti-fatigue properties, and is quite popular as a dietary supplement. AIM OF THE STUDY: This study was designed to offer a complementary and alternative medicine to manage the diabetic kidney disease (DKD), which causes long-term damage to the renal structure. We also investigated the regulation of the autophagy mechanism, which is the underlying the pathogenesis of DKD. MATERIALS AND METHODS: The effect of Korean red ginseng (KRG) on DKD was evaluated using human kidney proximal tubular cells and streptozotocin (STZ)-treated Sprague-Dawley rat models. In vitro experiments were conducted to evaluate the proteins related to fibrosis and autophagy. This was followed by in vivo experiments involving rats treated with single intraperitoneal administration of STZ (60 mg/kg) and then with KRG solution orally for 4 weeks. Proteins related to renal injury, fibrosis, and autophagy were determined by immunoblotting. Hematoxylin and eosin (H&E), Periodic acid-Schiff (PAS), Sirius red, and immunostaining were processed for histological studies. RESULTS: KRG diminished the levels of metabolic measurements and blood parameters. Western blotting showed a decreased expression of proteins, such as TGF-ß1, KIM1, and AGE, which are responsible for renal inflammation, injury, and fibrosis. Histological studies also supported these results and revealed that the KRG-treated groups recovered from renal injury and fibrosis. Furthermore, the autophagy marker, LC3, was upregulated, whereas p62 was downregulated. The levels of proteins related to the autophagy mechanism, such as ATG7, increased, while mammalian target of rapamycin (mTOR) decreased with the KRG treatment and exhibited accelerated autophagy compared to the STZ alone group. CONCLUSIONS: KRG can suppress renal inflammation, injury, and fibrosis by blocking TGF-ß1 activation and can induce cellular autophagy. Therefore, this study strongly suggests that KRG exhibits a renoprotective effect against the STZ-induced DKD.

Oral Magnesium Supplementation Improved Lipid Profile but Increased Insulin Resistance in Patients with Diabetic Nephropathy: a Double-Blind Randomized Controlled Clinical Trial.

Low serum magnesium concentrations were associated with development of renal failure. We aimed to determine whether magnesium supplementation improves renal function, insulin resistance, and metabolic profiles in patients with diabetic nephropathy. A total of 80 hypomagnesemic patients diagnosed with type 2 diabetes and early-stage nephropathy were recruited. Subjects received either daily magnesium oxide or placebo for 12 weeks. Biochemical and anthropometric variables were measured. Physical activity and dietary intakes were also recorded. This study was approved by the ethics committee of Isfahan University of Medical Sciences and was registered on the Iranian Registry of Clinical Trials website (IRCT registration no. IRCT201404271485N12). Serum magnesium levels were not changed significantly. Although the supplementation did not influence glycemic indices, patients in the magnesium group had greater insulin resistance compared with the placebo group after intervention (0.3 ± 2.3 µIU/mL vs. - 0.04 ± 2.05, P = 0.04). No significant changes were observed in serum total cholesterol, triglycerides, HDL, LDL, and total cholesterol/HDL cholesterol ratio. Furthermore, magnesium did not affect inflammation, serum levels of creatinine, and blood urine nitrogen. However, a marginal decrease in microalbuminuria (- 3.1 ± 2.2 mg/L vs. - 14 ± 9.9, P = 0.09) was observed. Oral magnesium supplementation slightly improved microalbuminuria but resulted in increased insulin resistance in patients with diabetic nephropathy.

Jixuepaidu Tang-1 inhibits epithelial-mesenchymal transition and alleviates renal damage in DN mice through suppressing long non-coding RNA LOC498759.

Jixuepaidu Tang-1 is obtained from the decoction of the Chinese traditional medicinal plants including Centella asiatica, Astragalus membranaceus, and Sanguis draconis. Transforming growth factor-ß1 (TGF-ß1)/serum- and glucocorticoid-inducible kinase-1 (SGK1)-induced epithelial-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). In addition, long non-coding RNAs (lnRNAs) participate in the development of DN, but the role of lncRNA LOC498759 in DN is still unclear. This study aims to investigate the role of Jixuepaidu Tang-1 in regulating podocyte injury and renal damage in DN and to validate whether the mechanisms involve TGF-ß1/SGK1 signaling and LOC498759. The drug treatment was initiated 2 weeks after the DN modeling. The MTT method and TUNEL staining were used to measure cell viability and apoptosis, respectively. Immunofluorescence staining was used to detect the expression of nephrin and desmin in podocytes. Sera from the Jixuepaidu Tang-1-treated mice reversed the high glucose (HG)-induced podocyte injury and EMT in mouse podocytes. Further in vivo assay revealed that Jixuepaidu Tang-1 not only reduced the ratio of the kidney to body weight, 24 h-urine total protein, and blood glucose, but alleviated glomerular mesangial extracellular matrix deposition and glomerular cell apoptosis in the streptozotocin-induced DN mice. Mechanically, the mechanisms of Jixuepaidu Tang-1 may involve the suppression of EMT by inhibiting the TGF-ß1/SGK1-induced LOC498759 expression. Collectively, Jixuepaidu Tang-1 attenuates podocyte injury and renal damage in DN, and inhibits EMT through suppressing TGF-ß1/SGK1-LOC498759 signaling.

Differences in Serum Amino Acid Phenotypes Among Patients with Diabetic Nephropathy, Hypertensive Nephropathy, and Chronic Nephritis.

BACKGROUND We assessed levels of circulating amino acids in different etiologies of chronic kidney disease (CKD) and the association of amino acids with risk factors of CKD progression. MATERIAL AND METHODS High-performance liquid chromatography-based analysis was used to determine amino acid profiles in patients with diabetic nephropathy (DN, n=20), hypertensive nephropathy (HN, n=26), and chronic nephritis (CN, n=33), and in healthy controls (HC, n=25). RESULTS All 3 types of CKD patients displayed decreased serum levels of serine, glycine, GABA, and tryptophan compared with healthy controls. Moreover, serine and tryptophan were positively correlated with glucose in DN cohorts. Total cholesterol was positively correlated with tryptophan levels in the DN cohort and negatively correlated with serine levels in the CN cohort. In the HN cohort, glycine was negatively correlated with triglyceride levels, and systolic blood pressure (SBP) was negatively correlated with GABA levels. CONCLUSIONS Patients with different etiologies of CKD have significantly different amino acids profiles, and this indicates specific supplementary nutritional needs in CKD patients.

The Effect of Iranian Propolis on Glucose Metabolism, Lipid Profile, Insulin Resistance, Renal Function and Inflammatory Biomarkers in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blind Clinical Trial.

Propolis is a natural product with many biological properties including hypoglycemic activity and modulating lipid profile. The present study was designed to evaluate the effect of Iranian propolis extract on glucose metabolism, Lipid profile, Insulin resistance, renal and liver function as well as inflammatory biomarkers in patients with type 2 diabetes mellitus (T2DM). A double-blind, placebo-controlled clinical trial was conducted. The duration of the study lasted 90 days. Patients with T2DM were recruited and randomly divided into an Iranian propolis group (1000 mg/day) (n = 50) and a placebo group (n = 44). There was a significant decrease in the serum levels of glycosylated hemoglobin (HbA1c), 2-hour post prandial (2hpp), insulin, homeostasis model assessment-insulin resistance (HOMA-IR), homeostasis model assessment of ß-cell function (HOMA-ß), High sensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α). However, there was a notable elevation in the serum HDL-C in the propolis group compared with the placebo group. In addition, a notable reduction in serum liver transaminase (ALT and AST) and blood urea nitrogen (BUN) concentrations in the propolis group was observed. Iranian propolis has beneficial effects on reducing post prandial blood glucose, serum insulin, insulin resistance, and inflammatory cytokines. It is also a useful treatment for preventing the liver and renal dysfunction, as well as, elevating HDL-C concentrations in patients with T2DM.

Dianthus superbus Improves Glomerular Fibrosis and Renal Dysfunction in Diabetic Nephropathy Model.

Glomerular fibrosis is caused by an accumulation of intercellular spaces containing mesangial matrix proteins through either diffused or nodular changes. Dianthus superbus has been used in traditional medicine as a diuretic, a contraceptive, and an anti-inflammatory agent. The aim of this study was to investigate the effects of Dianthus superbus-EtOAc soluble fraction (DS-EA) on glomerular fibrosis and renal dysfunction, which has been implicated in diabetic nephropathy in human renal mesangial cells and db/db mice. DS-EA was administered to db/db mice at 10 or 50 mg/kg/day for 8 weeks. DS-EA treatment significantly ameliorated blood glucose, insulin, the homeostasis model assessment of insulin resistance (HOMA-IR) index, and HbA1c in diabetic mice. DS-EA decreased albumin excretion, creatinine clearance (Ccr), and plasma creatinine levels. DS-EA also ameliorated the levels of kidney injury molecules-1 (KIM-1) and C-reactive protein. DS-EA reduced the periodic acid-Schiff (PAS) staining intensity and basement membrane thickening in glomeruli of the diabetic nephropathy model. In addition, DS-EA suppressed transforming growth factor-ß (TGF-ß)/Smad signaling. Collagen type IV, a glomerular fibrosis biomarker, was significantly decreased upon DS-EA administration. DS-EA pretreatment attenuated levels of inflammation factors such as intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). DS-EA inhibited the translocation of nuclear factor kappa B (NF-κB) in Angiotensin II (Ang II)-stimulated mesangial cells. These findings suggest that DS-EA has a protective effect against renal inflammation and fibrosis. Therefore, DS-EA may serve as a potential therapeutic agent targeting glomerulonephritis and glomerulosclerosis, which lead to diabetic nephropathy.

Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells.

Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.