24-h Urinary Albumin Excretion Rate Research Articles

PS-C33-11: FACTORS RELATED TO DETERIORATED KIDNEY FUNCTION IN RESISTANT HYPERTENSION PATIENTS

Objectives: To determine the factors associated with renal function deterioration in resistant hypertension (RH) patients Methods: The study included 152 patients aged 28 to 79 years with RH. They underwent measurement of office and ambulatory blood pressure monitoring (ABPM). Blood level of potassium, sodium, glucose, creatinine, uric acid, citrulline, C-reactive protein (CRP), matrix metalloproteinase-12 (MMP-12), aldosterone-renin ratio and 24-h excretion of metanephrine and 24-h urinary albumin excretion rate (AER) were determined. Glomerular filtration rate (GFR) was estimated by the CKD-EPI formula. Results: Chronic kidney disease (CKD) was diagnosed in 32.3% of patients with RH (gr.1 pts), gr.2 pts - those without CKD. Spearman's correlation analysis showed a negative relationship between GFR and office diastolic BP (DBP) and 24 hours mean DBP (r = -0.233; r = -0.373; P < 0.01, respectively). Significant negative correlation was revealed between GFR and daytime systolic BP variability (r = -0.275; P < 0.01). GFR was inversely related to AER (r = -0.412; P < 0.01), uric acid (r = -0.311; P < 0.05), CRP (r = -0.314; P < 0.05), MMP-12 (r = -0.385; P < 0.01), citrulline (r = -0.375; P < 0.01), sodium (r = -0.284; P < 0.05), aldosterone and urinary metanephrine level (r = -0.225; P < 0.05 and r = - 0.210; P < 0.05). In gr.1pts. level of CRP, MM-12 and citrulline was significantly (P < 0.01) higher than in the gr.2 pts. Factors independently and most closely related to reduced GFR in RH patients are 24 hours mean DBP (β; = -0.449, P < 0.001), CRP (β; = -0.354, P < 0.01), MMP-12 (β; = -0.248; P < 0.01) and citrulline (β; = -0.232; P < 0.05). Conclusions: Revealed associations, in addition to elevated blood pressure, indicate the possible pathogenic role of low-grade systemic inflammation biomarkers in the renal function deterioration in RH patients. Targeting low-grade systemic inflammation may improve BP control in resistant hypertension patients with CKD.

Benefits of SGLT2 inhibitors combining with renin–angiotensin-system blockers on cardiovascular outcomes in chronic kidney disease patients: A systemic review and meta-analysis

Background and objectiveEfficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin–angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients. MethodsWe searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords.“Renal Insufficiency, Chronic” or “Diabetic Nephropathies” and “Sodium-glucose cotransporter 2 inhibitors”. We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337. ResultsTen RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66–0.91, p=0.002; RR=0.7, 95% CI: 0.61–0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=−0.19, 95% CI: −0.24 to −0.14; RR=0.61, 95% CI: 0.51–0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59–0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=−5.4, 95% CI: −7.24 to −3.57), this effect was reversible. ConclusionsThese data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients.

POS-352 MiR-26a-5p PROTECTS PODOCYTE FROM APOPTOSIS VIA DOWNREGULATION OF TRPC6 IN TYPE 2 DIABETIC NEPHROPATHY

Podocyte injury is a major etiological factor in diabetic nephropathy (DN), while transient receptor potential cationic channel 6 protein (TRPC6) channels play a key role in podocyte injury. Our study is designed to investigate the regulatory effect of microRNA-26a-5p (miR-26a-5p) on DN podocyte injury induced by TRPC6 and the underlying mechanisms. 20 SPF, 8-week male Sprague-Dawley (SD) rats were used for establishing the type 2 diabetic mellitus (T2DM) group by feeding them with high fat and high sugar food for 8 weeks and intraperitoneal injection of low-dose streptozotocin (STZ, 30mg/kg). Another 10 normal male SD rats were selected as normal control group (NC). The 24h urinary albumin excretion rate (UAE), urinary creatinine (Ucr), creatinine clearance rate (CCr) and other major biochemical parameters including the fasting insulin level (FINS), serum creatinine (Scr), fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) were measured in both groups after establishing the DM models. Light and electron microscope were used to observe the pathology of kidneys and podocyte ultrastructures, respectively. Immunohistochemical method was used to show the distribution of nephrin and TRPC6 protein. To determine the expression of nephrin, TRPC6, apoptotic-associated proteins (cleaved-caspase-3 and bax/bcl-2), western blot was applied. qRT-PCR was used to detect miR-26a-5p and mRNAs of nephrin, TRPC6, cleaved-caspase-3 and bax/bcl-2. Podocyte apoptotic rate was measured using TUNEL method. Cultured immortalized mouse podocytes (MPC5) were divided into three groups: normal glucose group (NG), hypertonic group (HM), high glucose group (HG). Before and after miR-26a-5p mimics and inhibitor transfecting, the expression and mRNAs of nephrin, TRPC6, cleaved-caspase-3 and bax/bcl-2 were detected again using the same methods. Flow cytometry (FCM) was uesd to detect podocyte apoptosis. 1. Compared with NC group, rats in DM group exhibited disrupted biochemical conditions, for uAER, CCr, FINS, FBG, TC, TG and LDL were all significantly increased (all P <0.05) while HDL were decreased (P <0.05), along with significant insulin resistance. 2. Increased glomeruli volume, mesangial cell proliferation, thickened basement membrane and foot process fusion could be observed by light and electron microscope. 3. Immunochemistry results showed a increased expression of TRPC6 and a decreased of nephrin in DM rats than those in NC group (both P <0.05). 4. Both qRT-PCR and Western blot results in vivo and in vitro showed a notable increase in the expression of TRPC6, cleaved-caspase-3 and bax/bcl-2 and decrease in the expression of nephrin and miR-26a-5p (P <0.05). TUNEL and flow cytometry indicated higher podocyte apoptosis in DM rats and HG group. 5. The expression of TRPC6, cleaved-caspase-3 and bax/bcl-2 were down-regulated and nephrin expression was restored after miR-26a-5p mimics transfection (all P <0.05), while miR-26a-5p inhibitor intervention could aggravate all above changes as the effects of HG on podocytes (all P <0.05). High-glucose condition significantly decreased miR-26a-5p expression and increased TRPC6 expression and podocyte apoptosis. In DN, miR-26a-5p can protect podocyte from apoptosis via down-regulating the expression of TRPC6.

Benefits of SGLT2 inhibitors combining with renin–angiotensin-system blockers on cardiovascular outcomes in chronic kidney disease patients: A systemic review and meta-analysis

Background and objectiveEfficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin–angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients. MethodsWe searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords.“Renal Insufficiency, Chronic” or “Diabetic Nephropathies” and “Sodium-glucose cotransporter 2 inhibitors”. We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337. ResultsTen RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66–0.91, p=0.002; RR=0.7, 95% CI: 0.61–0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=−0.19, 95% CI: −0.24 to −0.14; RR=0.61, 95% CI: 0.51–0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59–0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=−5.4, 95% CI: −7.24 to −3.57), this effect was reversible. ConclusionsThese data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients.

The expression of POMC and AgRP in brain and kidney tissues at different stages of diabetic nephropathy rats

Abstract Objective To explore the changes of proopiomelanocortin (POMC) and Agouti-Related Peptide (AgRP) expression in brain and kidney tissues under insulin intervention at different stages of diabetic nephropathy (DN) rats. Methods The male Sprague-Dawley (SD) rats of DN were treated with high-fat diet for 8 weeks and induced by intraperitoneally injection of streptozotocin (30 mg/kg) for one time. Then DN rats were also injected insulin subcutaneously at 2–5 U/(kg·24 h) from initiation of the streptozotocin. Kidney tissue, blood sample, and 24 h-urine were collected to detect the ratio of kidney/body weight, blood glucose and 24-h urinary albumin excretion rate at different stages (4, 8, 12, and 16 weeks). Immunohistochemistry assay was used to measure the expression of POMC and AgRP at different stages of DN rats. Results The DN rats were established successfully. With the progression of DN, blood glucose, 24-h urinary albumin excretion rate and kidney body weight ratio increased significantly, while decreased when insulin was injected. Immunohistochemistry showed that the expression levels of POMC were decreased gradually in brain and kidney tissues. Conversely, the expression of AgRP in kidney was highest at week 8 and then decreased gradually. The effect of insulin on normalizing POMC and AgRP expression in brain and renal tissues was also observed in DKD rats. Conclusion With the progression of DN, the expression of POMC and AgRP in kidney tissues was observed at different stages of disease, and their expressions were significantly normalized by insulin. The mechanism of in situ expression of POMC and AGRP in kidney to the progression of DN needs further investigations.

Alleviation of diabetic nephropathy by zinc oxide nanoparticles in streptozotocin-induced type 1 diabetes in rats.

This study examines the effect of nanoparticles with zinc oxides (ZnONPs) on diabetic nephropathy, which is the primary cause of mortality for diabetic patients with end‐stage renal disease. Diabetes in adult male rats was induced via intraperitoneal injection of streptozotocin. ZnONPs were intraperitoneally administered to diabetic rats daily for 7 weeks. Diabetes was associated with increases in blood glucose level, 24‐h urinary albumin excretion rate, glomerular basement membrane thickness, renal oxidative stress markers, and renal mRNA or protein expression of transforming growth factor‐β1, fibronectin, collagen‐IV, tumour necrosis factor‐α and vascular endothelial growth factor‐A. Moreover, the expression of nephrin and podocin, and the mRNA expression of matrix metalloproteinase‐9 were decreased in the diabetic group. These changes were not detected in the control group and were significantly prevented by ZnONP treatment. These results provide evidence that ZnONPs ameliorate the renal damage induced in a diabetic rat model of nephropathy through improving renal functionality; inhibiting renal fibrosis, oxidative stress, inflammation and abnormal angiogenesis; and delaying the development of podocyte injury. The present findings may help design the clinical application of ZnONPs for protection against the development of diabetic nephropathy.

Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease

Background: Cardiovascular outcomes in clinical trials with type 2 diabetes mellitus (T2DM) patients have shown that glucagon-like peptide-1 receptor agonist can have a beneficial effect on the kidney. This trial aimed to assess the effects of exenatide on renal outcomes in patients with T2DM and diabetic kidney disease (DKD). Methods: We performed a randomized parallel study encompassing 4 general hospitals. T2DM patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² and macroalbuminuria, defined as 24-h urinary albumin excretion rate (UAER) >0.3 g/24 h were randomized 1:1 to receive exenatide twice daily plus insulin glargine (intervention group) or insulin lispro plus glargine (control group) for 24 weeks. The primary outcome was the UAER percentage change from the baseline after 24 weeks of intervention. The rates of hypoglycemia, adverse events (AEs), and change in eGFR during the follow-up were measured as safety outcomes. Results: Between March 2016 and April 2019, 92 patients were randomized and took at least 1 dose of the study drug. The mean age of the participants was 56 years. At baseline, the median UAER was 1,512.0 mg/24 h and mean eGFR was 70.4 mL/min/1.73 m². After 24 weeks of treatment, the UAER percentage change was significantly lower in the intervention group than in the control group (p = 0.0255). Moreover, the body weight declined by 1.3 kg in the intervention group (the difference between the 2 groups was 2.7 kg, p = 0.0001). Compared to the control group, a lower frequency of hypoglycemia and more gastrointestinal AEs were observed in the intervention group. Conclusion: Exenatide plus insulin glargine treatment for 24 weeks resulted in a reduction of albuminuria in T2DM patients with DKD.

Reduced serum CTRP12 levels in type 2 diabetes are associated with renal dysfunction.

Serum C1q/TNF-related protein-12 (CTRP12) is one of the newly studied families of adipokines, which is believed to be associated with type 2 diabetes. However, the relationship between serum CTRP12 levels and diabetic nephropathy remains unclear. This study aimed to investigate the relationship between serum CTRP12 levels and renal function in patients with type 2 diabetes. A total of 115 type 2 diabetic patients and 54 healthy subjects were enrolled in this study. 52 patients with type 2 diabetes were in the diabetes group (T2DM). The 63 patients with renal dysfunction were diabetic nephropathy group (T2DM-DN) and were divided into microalbuminuria subgroup (31 cases) and macroalbuminuria subgroup (32 cases) according to the 24-h urine protein excretion rate. The concentrations of serum CTRP12 were determined by enzyme-linked immunosorbent assay. Serum CTRP12 level in T2DM and T2DM-DN groups was significantly lower compared with the control group, while CTRP12 level in T2DM-DN group was significantly lower than that in T2DM group, and was associated with the severity of renal insufficiency. After adjusting for gender and age, serum CTRP12 level was negatively correlated with the duration of diabetes, blood urea nitrogen (BUN), uric acid (UA) and 24-h urinary albumin excretion rate (UAE) in T2DM patients. Logistic regression analysis showed that serum CTRP12 level was significantly associated with renal dysfunction in type 2 diabetes mellitus. And the duration of diabetes, total cholesterol (CHOL) and neutrophils/lymphocytes (NLR) are independent risk factors for renal dysfunction in type 2 diabetes mellitus. Serum CTRP12 may be involved in the occurrence and development of diabetic nephropathy. Trial registration number and date of registration ChiCTR2000030794, March 14, 2020.

Melatonin Ameliorates Renal Fibrosis Through the Inhibition of NF-κB and TGF-β1/Smad3 Pathways in db/db Diabetic Mice

To investigate the effects and molecular mechanism of melatonin (MT) on NF-κB and TGF-β/Smad3 signaling pathways in db/db diabetic mice. db/db diabetic mice were divided into five groups treated with melatonin at doses of 50, 100, 200μg/kg, the urinary concentration was detected by ELISA, renal histology was observed in PAS paining. Mouse mesangial cells were divided into mannitol control group, normal control group, normal control+MT group, high glucose group, high glucose+different concentrations (10, 100, 1000) μmol/L MT group. The proliferation of mesangial cells was detected by EdU kit; the expression of NF-κBp65, ColⅣ and Fn were detected by laser confocal system; the concentrations and mRNA levels of ColⅣ and Fn were detected by ELISA and qRT-PCR. the expressions of ColⅣ, Fn, IκB, p-IκB, TGF-β1, Smad3 and p-Smad3 were detected by Western blot in renal tissues and mesangial cells. MT treatment could markedly improve the kidney histopathologic lesions. Compared with the db/m mice, 24h urinary albumin excretion rate (UAER) and the expressions of ColIV, Fn, p-IκB/IκB, NF-κBp65, TGF-β1 and p-Smad3/Smad3 were decreased after melatonin treatment (p <0.05). Compared with the control group, the proliferation function of mesangial cells in high glucose group was significantly enhanced, and the expressions of ColIV, Fn, p-IκB/IκB, NF-κBp65, TGF-β1 and p-Smad3/Smad3 in mesangial cells were significantly up-regulated (p <0.05), and these changes were significantly lowered in MT treatment. Melatonin can inhibit renal inflammation and fibrosis by inhibiting the NF-κB and TGF-β1/Smad3 signaling pathways, and melatonin may be a promising therapeutic target in diabetic nephropathy.

Gold nanoparticles attenuate albuminuria by inhibiting podocyte injury in a rat model of diabetic nephropathy

Several recent studies have reported that gold nanoparticles (AuNPs) attenuate hyperglycemia in diabetic animal models without any observed side effects. The present study was intended to provide insight into the effects of 50-nm AuNPs on diabetic kidney disease. Adult male rats were divided into three groups (n = 7/group): control (non-diabetic, ND), diabetic (D), and diabetic treated intraperitoneally with 50-nm AuNPs (AuNPs + D; 2.5 mg/kg/day) for 7 weeks. Diabetes was induced by a single-dose injection of 55 mg/kg streptozotocin. The result showed that AuNP treatment prevented diabetes-associated increases in the blood glucose level. Reduction in 24-h urinary albumin excretion rate, glomerular basement membrane thickness, foot process width, and renal oxidative stress markers was also demonstrated in the AuNP-treated group. In addition, the results showed downregulation effect of AuNPs in renal mRNA or protein expression of transforming growth factor β1 (TGF-β1), fibronectin, collagen IV, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor-A (VEGF-A). Moreover, the protein expression of nephrin and podocin, podocyte markers, in glomeruli was increased in the AuNPs + D group compared with the D group. These results provide evidence that 50-nm AuNPs can ameliorate renal damage in experimental models of diabetic nephropathy through improving the renal function and downregulating extracellular matrix protein accumulation, along with inhibiting renal oxidative stress and amelioration of podocyte injury.

Effect of baicalin on renal function in patients with diabetic nephropathy and its therapeutic mechanism.

The present study observed the effect of baicalin on blood glucose and renal function in patients with diabetic nephropathy and explored its mechanism of action. A total of 95 patients diagnosed with diabetic nephropathy by clinical and laboratory examinations were selected and randomly divided into a control and treatment group. The control group included 45 patients who were treated with routine symptomatic treatment. The remaining 50 patients in the treatment group received baicalin, in addition to routine symptomatic treatment. The treatment course was 6 months. Following this, the changes of indicators such as fasting plasma glucose (FPG), glycosylated hemoglobin (HBA1c), aldose reductase (AR) activity, 24-h urinary microalbumin, urinary β2-microglobulin (β2-MG) and urinary albumin excretion rate (UAER) were compared before and after treatment; at the same time, the variations of indexes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-px), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) were detected. Compared with those in the control group, baicalin had little effect on the treatment group's FPG and HBA1c, but it clearly reduced the AR activity and the difference was significant (P<0.05). Baicalin visibly decreased the 24-h urinary microalbumin, urinary β2-MG and UAER (P<0.05) and had notable effect on improving renal function. Following treatment, compared with those in the control group, baicalin distinctly increased the levels of SOD and GSH-px (P<0.05) and decreased the content of NF-κB and VEGF (P<0.05), however, its impact on the expression of TGF-β1 was not statistically significant (P>0.05). The results showed that baicalin may improve the renal function in patients with diabetic nephropathy and delay the progression of diabetic nephropathy through various ways, including anti-inflammation and anti-oxidation.

Evaluation of urinary biomarkers for prediction of diabetic kidney disease: a propensity score matching analysis.

Background:The aim of this study was to evaluate the diagnostic value of six urinary biomarkers for prediction of diabetic kidney disease (DKD).Methods:The cross-sectional study recruited 1053 hospitalized patients with type 2 diabetes mellitus (T2DM), who were categorized into the diabetes mellitus (DM) with normoalbuminuria (NA) group (n = 753) and DKD group (n = 300) according to 24-h urinary albumin excretion rate (24-h UAE). Data on the levels of six studied urinary biomarkers [transferrin (TF), immunoglobulin G (IgG), retinol-binding protein (RBP), β-galactosidase (GAL), N-acetyl-beta-glucosaminidase (NAG), and β2-microglobulin (β2MG)] were obtained. The propensity score matching (PSM) method was applied to eliminate the influences of confounding variables.Results:Patients with DKD had higher levels of all six urinary biomarkers. All indicators demonstrated significantly increased risk of DKD, except for GAL and β2MG. Single RBP yielded the greatest area under the curve (AUC) value of 0.920 compared with the other five markers, followed by TF (0.867) and IgG (0.867). However, GAL, NAG, and β2MG were shown to have a weak prognostic ability. The diagnostic values of the different combinations were not superior to the single RBP.Conclusions:RBP, TF, and IgG could be used as reliable or good predictors of DKD. The combined use of these biomarkers did not improve DKD detection.

Taxus chinensis ameliorates diabetic nephropathy through down-regulating TGF-β1/Smad pathway

Diabetic nephropathy (DN) is one of the common microvascular complications of diabetes mellitus. Renal fibrosis is closely related to the deterioration of renal function. The present study aimed to investigate protective effect of Taxus chinensis on high-fat diet/streptozotocin-induced DN in rats and explore the underlying mechanism of action. The rat DN model was established via feeding high fat diet for 4 weeks and subsequently injecting streptozotocin (30 mg·kg−1 body weight) intraperitoneally. The rats with blood glucose levels higher than 16.8 mmol·L−1 were selected for experiments. The DN rats were treated with Taxus chinensis orally (0.32, 0.64, and 1.28 g·kg−1) once a day for 8 weeks. Taxus chinensis significantly improved the renal damage, which was indicated by the decreases in 24-h urinary albumin excretion rate, blood serum creatinine, and blood urea nitrogen. Histopathological examination confirmed the protective effect of Taxus chinensis. The thickness of glomerular basement membrane was reduced, and proliferation of mesangial cells and podocytes cells and increase in mesangial matrix were attenuated. Further experiments showed that Taxus chinensis treatment down-regulated the expression of TGF-β1 and α-SMA, inhibited phosphorylation of Smad2 and Smad3. These results demonstrated that Taxus chinensis alleviated renal injuries in DN rats, which may be associated with suppressing TGF-β1/Smad signaling pathway.

QiDiTangShen Granules Reduced Diabetic Kidney Injury by Regulating the Phosphorylation Balance of the Tyrosine and Serine Residues of Insulin Receptor Substrate 1.

Background Diabetic nephropathy (DN) is a microvascular complication induced by diabetes mellitus (DM), which can affect life quality and long-term prognosis of patients with DM. Angiotensin-converting-enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) are currently recommended for treating DN proteinuria, but patients receiving ACEI/ARB are at risk of elevated serum creatinine or potassium levels. Based on the “yin-yang” theory of traditional Chinese medicine, the present study explored the effect of QiDiTangShen (QDTS) granules on DN and the phosphorylation balance of tyrosine and serine residues of IRS-1. Methods In this experiment, db/db mice were used as an animal model for type 2 diabetic nephropathy. The intervention (QDTS granules and valsartan) started when the mice were 12 weeks old. C57BL/6 mice were used as normal control. The urine albumin excretion ratio (UAER) was measured by enzyme-linked immunosorbent assay (ELISA) before and after the intervention. The IRS-1, PI3K, Akt, and MAPK proteins expression and the phosphorylation levels were detected by western blot. Results QDTS granules reduced the 24-h urinary albumin excretion rate (UAE) in db/db mice with type 2 DM and attenuated the pathological changes of the kidney. QDTS granules also increased the activation level of the PI3K/Akt signaling pathway and reduced insulin resistance. In addition, QDTS granules inhibited the activation of ERK and p38MAPK and decreased the phosphorylation ratio of Ser307/Tyr896 of IRS-1 in renal tissue. Conclusions QDTS granules reduced DM-induced renal injury by improving insulin sensitivity via suppressing MAPK signaling and restoring the phosphorylation balance of tyrosine/serine of IRS-1.

The effect of liraglutide on renal function: A randomized clinical trial.

Among patients with type 2 diabetes and albuminuria, cardiorenal morbidity and mortality are high despite multifactorial treatment. Short-term reduction in albuminuria is considered suggestive of long-term renoprotective effects. We evaluated the renal effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on top of multifactorial care, including renin-angiotensin-system (RAS)-inhibition. Randomized, double-blind, placebo-controlled, cross-over trial including patients with type 2 diabetes and persistent albuminuria (urinary albumin-to-creatinine ratio >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 . Patients received liraglutide (1.8 mg/d) and matched placebo for 12 weeks in a random order. The primary endpoint was change in 24-h urinary albumin excretion rate (UAER). A total of 32 patients were randomized and 27 completed the study. After placebo treatment, geometric mean (IQR) UAER was 199 (81-531) mg/24-h, mean (SD) measured GFR (mGFR) 75 (36) mL/min/1.73 m2 , 24-h blood pressure 145/80 (15/8) mm Hg and HbA1c 61 (11) mmol/mol. Liraglutide reduced HbA1c by 8 (95% CI: 5; 11) mmol/mol (P < .001) and weight by 1.8 (95% CI: 0.2; 3.4) kg (P = .032) compared to placebo. Furthermore, liraglutide reduced UAER by 32 (95% CI: 7; 50)% ( P = .017) compared with placebo. The change in mGFR was -5 (95% CI: -11; 2) mL/min/1.73 m2 ( P = .15), and change in 24-h systolic blood pressure was -5 (95% CI: -10; 0) mm Hg ( P = .07). In multivariate regression models, change in UAER was associated with change in 24-h systolic blood pressure ( P = .025) but not with change in HbA1c, weight or mGFR ( P ≥ .14), overall model R 2 = .39. Our placebo-controlled randomized trial suggests that liraglutide has renoprotective effects on top of multifactorial treatment, including RAS-inhibition, in patients with type 2 diabetes and albuminuria.

FK506 reduces albuminuria through improving podocyte nephrin and podocin expression in diabetic rats.

Objective and designSeveral works in the setting of early experimental diabetic nephropathy using anti-inflammatory drugs, such as the calcineurin inhibitor FK506, have shown prevention of the development or amelioration of renal injury including proteinuria. The exact mechanisms by which anti-inflammatory drugs lower the albuminuria have not been still clarified well.MaterialsThe diabetic rats were induced by using streptozotocin.TreatmentThe diabetic rats were subjected to oral FK506 treatment at a dose of 0.5 or 1.0 mg/kg daily for 4 weeks.MethodsRenal histology for the ultrastructural evaluation was determined by electron microscope, followed by analyses of renal nephrin and podocin and detection of renal iNOS+ macrophages and NF-κB-p-p65+.ResultsElevated 24-h urinary albumin excretion rate was markedly attenuated by FK506 treatment. In diabetic model rats, FK506 treatment at a dose of 0.5 or 1.0 mg/kg significantly increased the expression of nephrin and podocin when compared to control. As expected, rats in control diabetic group had an increase in GBM thickening and foot process effacement when compared to normal rats; increased GBM thickening and foot process effacement were ameliorated by FK506 treatment with 0.5 and 1.0 mg/kg. Histologically, there was marked accumulation of ED-1+cells (macrophages) in diabetic kidneys, and FK506 treatment failed to inhibit it. In contrast, FK506 treatment at 0.5 and 1.0 mg/kg doses significantly inhibited the elevated ED-1+/iNOS+ cells in the kidneys of diabetic rats. ED-1+/NF-κB-p-p65+ cells were significantly increased in positive diabetic kidneys compared to those of normal rats. FK506 treatment at 0.5 and 1.0 mg/kg significantly attenuated the elevated ED-1+/NF-κB-p-p65+ cells in diabetic kidneys. Additionally, a positive correlation was observed between ED-1+/iNOS+ cells and albuminuria (r = 0.87, p < 0.05). Likewise, ED-1+/iNOS+ cells were correlated negatively with both nephrin and podocin protein (r = −0.70, p < 0.05; r = −0.68, p < 0.05, respectively).ConclusionOur results show that FK506 not only upregulates expression of nephrin and podocin but also inhibits macrophage activation to protect against podocyte injury.

Protective effect of total flavonoids extracted from the leaves of Murraya paniculata (L.) Jack on diabetic nephropathy in rats

This study was designed to evaluate the effects of total flavonoids extracted from the leaves of Murraya paniculata (L.) Jack (TFMP) on diabetic nephropathy.High fat diet and streptozotocin-induced diabetic rats were treated with the TFMP (35 or 70mg/kg) for 13weeks. Changes of renal function parameters were examined at the end of administration. Some kidneys were collected for histological and immunohistochemistry studies, the other ones for biochemical parameters analysis.TFMP significantly decreased the levels of serum blood urea nitrogen, serum creatinine, creatinine clearance, interleukin-6, urinary albumin, 24h-urinary albumin excretion rate, kidney weight to body weight ratio and fasting blood glucose in diabetic rats. Meanwhile, the levels of triglycerides, total and LDL cholesterols in the TFMP treated diabetic rats were lower and the high-density lipoprotein cholesterol level was higher than that in the diabetic rats. TFMP treatment significantly blocked the decrease of superoxide dismutase and glutathione peroxidase and increase of malondialdehyde levels in diabetic rats. Furthermore, the TFMP not only decreased the expression of TGF-β1 and CTGF protein, but also reduced diabetes-induced morphological alterations of the kidney. These results suggest that TFMP is a protective agent against renal damage in diabetic nephropathy.

Total Glucosides of Paeony Regulates JAK2/STAT3 Activation and Macrophage Proliferation in Diabetic Rat Kidneys

Total glucosides of paeony (TGP) is the major active constituent of Paeonia lactiflora Pall., which has shown renoprotection in experimental diabetic nephropathy. Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage. Macrophages also play an essential role in the pathogenesis of diabetic nephropathy. Herein, we investigated the ability of TGP to modulate JAK2/STAT3 activation and macrophage proliferation in rats with streptozotocin (STZ)-induced diabetes. TGP (50, 100, and 200 mg/kg) was administered orally once a day for eight weeks. Levels of p-JAK2 and p-STAT3 were determined by Western blot analysis. Immunohistochemistry and double immunohistochemistry were used to identify p-STAT3, ED-1, PCNA/ED-1, and p-STAT3/ED-1-positive (+) cells. The elevated 24-h urinary albumin excretion rate was markedly attenuated by treatment with 50, 100, and 200 mg/kg TGP. Western blot analysis showed that the significantly increased levels of p-JAK2, p-STAT3 proteins in the kidneys of diabetic rats were significantly inhibited by 50, 100, and 200 mg/kg TGP treatment. The marked accumulation and proliferation of macrophages in diabetic kidneys were significantly inhibited by TGP treatment. ED-1+/p-STAT3+ cells were significantly increased in the kidneys from the model group but were significantly inhibited by TGP treatment. These results show that TGP significantly inhibited diabetic nephropathy progression and suggest that these protective effects are associated with the ability of TGP to inhibit the JAK2/STAT3 pathway and macrophage proliferation and action.

Angelica Acutiloba Root Alleviates Advanced Glycation End‐Product‐Mediated Renal Injury in Streptozotocin‐Diabetic Rats

Angelica acutiloba root, a Japanese species of Dong quai being cultivated in Hualien County in eastern Taiwan, is used primarily for gynecological disorders in women. Increasing evidence indicates that advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic nephropathy. We investigated whether A. acutiloba root is beneficial in the amelioration of AGE-mediated renal injury in a diabetic rat model. Streptozotocin (STZ)-diabetic rats were treated orally with A. acutiloba root extract (AARE) [50, 100, 200 mg/(kg × day)] for 8 wk. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for enzyme immunoassay, pathology histology, immunohistochemistry, and Western blot analyses. Polyphenolic compounds and flavonoids were abundant in AARE. AARE [200 mg/(kg × day)] partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-h urinary albumin excretion rate, creatinine clearance, and glomerular mesangial matrix expansion were ameliorated by AARE treatment. The increased expression of nuclear factor-κB, transforming growth factor-β(1), and the progressive accumulation of fibronectin in kidney of diabetic rats were attenuated by AARE treatment. AARE treatment ameliorated the elevated levels of advanced glycation end products (AGEs) and mitochondrial thiobarbituric acid-reactive substance, as well as the elevated levels of Nε-(carboxymethyl)lysine and receptors for AGEs in kidneys of diabetic rats. The results show that A. acutiloba root has an anti-diabetic property that involves antihyperglycemia accompanied by amelioration of glycation-mediated renal damage.

The amelioration of streptozotocin diabetes-induced renal damage by Wu-Ling-San (Hoelen Five Herb Formula), a traditional Chinese prescription

Ethnopharmacological relevance Wu-Ling-San (Hoelen Five Herb Formula) is a Chinese prescription used to promote water metabolism. Aim of the study The present study was undertaken to characterize the effects of Wu-Ling-San on diabetic nephropathy. Materials and methods Streptozotocin (STZ)-diabetic rats were orally administrated with Wu-Ling-San (0.5, 1.5, 2.5 g/(kg day)) once a day for 10 weeks. Changes in the renal function related parameters in plasma and urine were analyzed at the end of 10-week administration. Kidney was isolated for pathology histology, immunohistochemistry staining and Western blot analyses. Results Wu-Ling-San (2.5 g/(kg day)) partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-h urinary albumin excretion rate, creatinine clearance, and glomerular mesangial matrix expansion were ameliorated by Wu-Ling-San. The increased expression of nuclear factor-kB as well as transforming growth factor-β 1 and the progressive accumulation of fibronectin in kidney of diabetic rats were attenuated by Wu-Ling-San. Not only the elevated levels of advanced glycation end products (AGEs) and mitochondrial thiobarbituric acid-reactive substance, but also the higher levels of N ɛ-(carboxymethyl)lysine and receptor for AGEs in kidney of diabetic rats were ameliorated by Wu-Ling-San. Conclusions : Wu-Ling-San posses an anti-diabetic property with plasma glucose lowering action accompanied with amelioration of glycation-mediated renal damage.