Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVß3 integrin cross talk.

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) regulates angiogenesis via effects on extracellular matrix proteolysis and cell adhesion. However, no previous study has implicated PAI-1 in controlling vascular endothelial growth factor (VEGF) signaling. We tested the hypothesis that PAI-1 downregulates VEGF receptor-2 (VEGFR-2) activation by inhibiting a vitronectin-dependent cooperative binding interaction between VEGFR-2 and αVß3. APPROACH AND RESULTS: We studied effects of PAI-1 on VEGF signaling in human umbilical vein endothelial cells. PAI-1 inhibited VEGF-induced phosphorylation of VEGFR-2 in human umbilical vein endothelial cells grown on vitronectin, but not on fibronectin or collagen. PAI-1 inhibited the binding of VEGFR-2 to ß3 integrin, VEGFR-2 endocytosis, and intracellular signaling pathways downstream of VEGFR-2. The anti-VEGF effect of PAI-1 was mediated by 2 distinct pathways, one requiring binding to vitronectin and another requiring binding to very low-density lipoprotein receptor. PAI-1 inhibited VEGF-induced angiogenesis in vitro and in vivo, and pharmacological inhibition of PAI-1 promoted collateral arteriole development and recovery of hindlimb perfusion after femoral artery interruption. CONCLUSIONS: PAI-1 inhibits activation of VEGFR-2 by VEGF by disrupting a vitronectin-dependent proangiogenic binding interaction involving αVß3 and VEGFR-2. These results broaden our understanding of the roles of PAI-1, vitronectin, and endocytic receptors in regulating VEGFR-2 activation and suggest novel therapeutic strategies for regulating VEGF signaling.

Dietary interventions for mineral and bone disorder in people with chronic kidney disease.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic dysfunction of mineral and bone metabolism in people with CKD. Recent research shows that phosphate retention plays a significant role in the development of CKD-MBD. Compared with drug therapies, dietary interventions may be simple, inexpensive and feasible for phosphate retention. However, there is little evidence to support these interventions. OBJECTIVES: Our objective was to assess the benefits and harms of any dietary intervention for preventing and treating CKD-MBD. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register to 27 August 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We also searched the Chinese Biomedicine Database (CBM) (1976 to August 2015), China Knowledge Resource Integrated Database (CNKI) (1979 to August 2015), and VIP (1989 to August 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs looking at dietary interventions for prevention or treatment of CKD-MBD were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the eligibility, methodological quality, and extracted data. Continuous outcomes (serum calcium level, serum phosphorus level, calcium × phosphate product, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23) and alkaline phosphatase) were expressed as mean difference (MD) with 95% confidence interval (CI). Dichotomous outcomes (mortality) were expressed as risk ratio (RR) with 95% CI. We used a random-effects model to meta-analyse studies. MAIN RESULTS: Nine studies were included in this review which analysed 634 participants. Study duration ranged from 4 to 24 weeks. The interventions included calcium-enriched bread, low phosphorus intake, low protein intake, very low protein intake, post haemodialysis supplements and hypolipaemic diet. Only one study reported death; none of the included studies reported cardiovascular events or fractures. There was insufficient reporting of design and methodological aspects among the included studies to enable robust assessment of risk of bias.There was limited and low-quality evidence to indicate that calcium-enriched bread increased serum calcium (1 study, 53 participants: MD -0.16 mmol/L, 95% CI -0.51 to -0.31), decreased serum phosphorus (53 participants: MD -0.41 mmol/L, 95% CI -0.51 to -0.31) and decreased the calcium × phosphate product (53 participants: MD -0.62 mmol²/L², 95% CI -0.77 to -0.47).Very low protein intake was not superior to conventional low protein intake in terms of effect on serum phosphorus (2 studies, 41 participants: MD -0.12 mmol/L, 95% CI -0.50 to 0.25), serum calcium (MD 0.00 mmol/L, 95% CI -0.17 to 0.17), or alkaline phosphatase (MD -22.00 U/L, 95% CI -78.25 to 34.25). PTH was significantly lower in the very low protein intake group (2 studies, 41 participants: MD -69.64 pmol/L, 95% CI -139.83 to 0.54).One study reported no significant difference in the number of deaths between low phosphorus intake and normal diet (279 participants: RR 0.18, 95% CI 0.01 to 3.82). Low phosphorus intake decreased serum phosphorus (2 studies, 359 participants: MD -0.18 mmol/L, 95% CI -0.29 to -0.07; I(2) = 0%).One study reported post-haemodialysis supplements did not increase serum phosphorus compared to normal diet (40 participants: MD 0.12 mmol/L, 95% CI -0.24 to 0.49).One study reported low phosphorus intake plus lanthanum carbonate significantly decreased FGF-23 (19 participants: MD -333.80 RU/mL, 95% CI -526.60 to -141.00), but did not decrease serum phosphorus (19 participants: MD -0.10 mg/dL, 95% CI -0.38 to 0.58) or PTH (19 participants: MD 31.60 pg/mL, 95% CI -29.82 to 93.02). AUTHORS' CONCLUSIONS: There was limited low quality evidence to indicate that dietary interventions (calcium-enriched bread or low phosphorus/protein intake) may positively affect CKD-MBD by increasing serum calcium, decreasing serum phosphorus, the calcium × phosphate product and FGF-23. Large and well-designed RCTs are needed to evaluate the effects of various interventions for people with CKD-MBD.

Effects of a Chinese herbal extract on the intestinal tract and aquaporin in Adriamycin-induced nephropathy.

Wuling Decoction is a traditional Chinese medicine that has been used to open knots, benefit water, transform Qi, return fluid, and has a significant effect on strengthening the spleen and removing dampness. To explore the effects of Wuling Decoction on the intestinal tract and aquaporin in Adriamycin-induced nephropathy, 45 specific pathogen free (SPF) Wistar rats were randomly divided into a blank control group (5 rats), Dosing control group (10 rats), Adriamycin nephropathy model group (10 rats), diarrhea group (10 rats), and an Adriamycin nephropathy diarrhea model group (10 rats). The tissue localization of aquaporin (AQP) was determined by immunohistochemistry. The expression of AQP mRNA and protein was measured by RT-PCR and western blot analysis, respectively. The results indicated that Wuling Decoction causes excretion of AQP2 through the urine, regulates AQP2 levels, and exerts diuretic and anti-diarrheal effects. It also regulates the levels of antidiuretic hormone (ADH) and arginine vasopressin (AVP), affects water absorption rate, and reduces the level of cyclic adenosine monophosphate (cAMP) in each tissue, thus reducing the absorption of AQP2 to water. Wuling Decoction promoted AQP2 expression in the nephropathy model group and inhibited AQP2 expression in the diarrhea group. Wuling Decoction increased the expression of aquaporin in the intestinal tract, reduced the water content of stool by promoting the absorption of water in the intestinal tract, inhibited the expression of aquaporin and its regulatory factors in nephridia tissue, and reduced the reabsorption of water to increase urine volume, to decrease the occurrence of diarrhea.

Real-World Effects of Chinese Herbal Medicine for Idiopathic Membranous Nephropathy (REACH-MN): Protocol of a Registry-Based Cohort Study.

Introduction: Some encouraging findings of Chinese herbal medicine (CHM) in management of idiopathic membranous nephropathy (IMN) obtained in the setting of clinical trials are hard to validate in the daily clinical practice due to a complicated treatment scenario of CHM in practice. The primary objective of this registry is to provide a description of treatment patterns used in management of IMN and assess clinical remission in daily practice in a Chinese population sample with IMN. Methods and analysis: This is a prospective, multicenter cohort which will comprise 2000 adults with IMN regardless of urinary protein levels that will be recruited from 11 nephrology centers across China. The participants will be followed for up to at least 2 years. Primary outcome is composite remission (either complete remission or partial remission) 24 months after enrolment. The secondary outcomes are complete remission, partial remission, time to remission, no response, relapse, proteinuria, annual change of glomerular filtration rate, antibodies against PLA2R, and composite endpoint of 40% reduction of glomerular filtration rate, doubling of serum creatinine, end-stage renal disease, and death. Propensity score analysis will be used for matching and adjustment. Ethics and dissemination: This study has been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (BF2020-094-01). Results of the study will be published in both national and international peer-reviewed journals, and presented at scientific conferences. Investigators will inform the participants as well as other IMN patients of the findings via health education. Study registration: ChiCTR2000033680 (prospectively registered).

Platelet-derived miR-103b as a novel biomarker for the early diagnosis of type 2 diabetes.

AIMS: MicroRNA-103 (miR-103) plays a critical role in regulating glucose homeostasis in type 2 diabetes (DM2). Recent data suggest that secreted frizzled-related protein 4 (SFRP4) serves as a potential risk biomarker for prediabetic mellitus (pre-DM) and that platelets are enriched for miR-103. The objective of this study was to test the hypothesis that platelet-derived miR-103b (miR-103-as), which regulates SFRP4, might be a novel biomarker for the early diagnosis of DM2. METHODS: We evaluated platelet miR-103b expression in healthy subjects (n = 46), pre-DM subjects (n = 48), non-complicated diabetic subjects (n = 43) and diabetes mellitus type 2-coronary heart disease subjects (n = 36), respectively, and analyzed the relationship of these levels with its target gene SFRP4. RESULTS: In qRT-PCR assays, miR-103b were significantly down-regulated, and conversely, the expression of the SFRP4 gene was up-regulated in pooled leukocyte-depleted platelets and individual subjects with pre-DM. Additionally, patients who had undergone antiplatelet treatment were characterized by decreased gene expression of SFRP4 and increased levels of platelet-derived miR-103b. miR-103b modulated reporter gene expression through SFRP4 mRNA 3'-UTR seed sequence and negatively regulated its expression. Furthermore, SFRP4 mRNA and protein levels were down-regulated by a miR-103b mimic but were up-regulated by a miR-103b inhibitor. CONCLUSIONS: The results suggest that platelet-derived miR-103b could negatively regulate the expression of SFRP4 mRNA/protein in pre-DM2, indicating that miR-103b could be a novel biomarker for the early diagnosis of DM2.