scholarly journals Study on Association of Pentraxin 3 and Diabetic Nephropathy in a Rat Model

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xuehai Chen ◽  
Jiao Luo ◽  
Minmin Wu ◽  
Zhuo Pan ◽  
Yue Xie ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Islet Transplantation ◽  
Renal Injury ◽  
Microvascular Disease ◽  
Renal Tissue ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Tubular Injury ◽  
Clinical Progression ◽  
Renal Tubular

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Compared with other therapies for diabetic patients, islet transplantation can effectively prevent and reverse diabetes-induced microvascular disease, such as diabetic retinopathy and nephropathy. PTX3 is the only long pentraxin that can be detected in renal tissue. In this study, we investigated the expression of PTX3 when early DN was reversed after islet transplantation.Methods. Diabetes was induced in rats by injecting streptozotocin (STZ). Twelve weeks later, the diabetic rats were divided into 2 groups: the islet transplantation group (IT) and the diabetic nephropathy group (DN). Renal injury, renal function, and the expression of PTX3 in the plasma and the kidneys were assessed with urinalysis, immunohistochemical staining, and Western blot, respectively.Results. The expression of PTX3 in the kidney was significantly decreased in the DN group but increased in the IT group because of the reversal of DN.Conclusions. Our data showed that the level of PTX3 in renal tissue is closely related to renal injury in DN. This may be used to quantify the extent of renal injury in DN, provide a potential early indicator of renal tubular injury in early DN patients, and assess DN clinical progression.

scholarly journals Tumor necrosis factor-α blockade ameliorates diabetic nephropathy in rats

2019 ◽  
Author(s):  
Dongsheng Cheng ◽  
Rulian Liang ◽  
Baorui Huang ◽  
Jiasheng Hou ◽  
Jianyong Yin ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tumor Necrosis Factor ◽  
Nlrp3 Inflammasome ◽  
Tumor Necrosis ◽  
Critical Role ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Tubular Injury ◽  
Tnf Α ◽  
Necrosis Factor

Abstract Background Tubular injury plays a critical role in the development of diabetic nephropathy (DN), but current DN therapies do not combat tubular injury. This study was conducted to investigate if tumor necrosis factor (TNF)-α inhibition protects against tubular injury in diabetic rats and to examine the associated mechanisms. Methods Kidney biopsy tissues were collected and analyzed from 12 patients with DN and 5 control subjects. Streptozotocin (STZ)-induced diabetic rats were treated with a TNF-α inhibitor for 12 weeks. Renal function, albuminuria, histological injury, renal TNF-α messenger RNA (mRNA) and the NOD- (nucleotide-binding), LRR- (domain-like receptor) and pyrin domain-containing protein 3 (NLRP3) inflammasome were assessed. Results Diabetic patients with tubulointerstitial injury (TIN) presented with higher renal tubular expression of TNF-α mRNA and the NLRP3 inflammasome (P < 0.05). TNF-α inhibition reduced albuminuria, glomerular injury and tubular injury in STZ-induced diabetic rats (P < 0.05). Importantly, TNF-α inhibition significantly reduced the NLRP3 inflammasome in tubules (P < 0.05). Moreover, TNF-α inhibition decreased expression of tubular interleukin (IL)-6 and IL-17A mRNA. Conclusions TNF-α inhibition protects against TIN by suppressing the NLRP3 inflammasome in DN rats. Future studies may focus on the clinical protective effects of TNF-α inhibition using prospective observation.

scholarly journals Role of Dendritic Cell in Diabetic Nephropathy

2021 ◽  
Vol 22 (14) ◽  
pp. 7554
Author(s):  
Hyunwoo Kim ◽  
Miyeon Kim ◽  
Hwa-Young Lee ◽  
Ho-Young Park ◽  
Hyunjhung Jhun ◽  
...  
Keyword(s):  
T Cells ◽  
Diabetic Nephropathy ◽  
Microvascular Complications ◽  
Treatment Options ◽  
Renal Tissue ◽  
Current Treatment ◽  
Diabetic Patients ◽  
Activated T Cells ◽  
Stage Renal Disease ◽  
Incident Cases

Diabetic nephropathy (DN) is one of the most significant microvascular complications in diabetic patients. DN is the leading cause of end-stage renal disease, accounting for approximately 50% of incident cases. The current treatment options, such as optimal control of hyperglycemia and elevated blood pressure, are insufficient to prevent its progression. DN has been considered as a nonimmune, metabolic, or hemodynamic glomerular disease initiated by hyperglycemia. However, recent studies suggest that DN is an inflammatory disease, and immune cells related with innate and adaptive immunity, such as macrophage and T cells, might be involved in its development and progression. Although it has been revealed that kidney dendritic cells (DCs) accumulation in the renal tissue of human and animal models of DN require activated T cells in the kidney disease, little is known about the function of DCs in DN. In this review, we describe kidney DCs and their subsets, and the role in the pathogenesis of DN. We also suggest how to improve the kidney outcomes by modulating kidney DCs optimally in the patients with DN.

scholarly journals Amelioration of neuropilin-1 and rage/matrix metalloproteinase-2 pathway-induced renal injury in diabetic rats by rosuvastatin

2021 ◽  
pp. 21-21
Author(s):  
Rabia Nabi ◽  
Sultan Alvi ◽  
Sultan Alouffi ◽  
Saif Khan ◽  
Adnan Ahmad ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Renal Injury ◽  
Reductase Activity ◽  
Renal Tissue ◽  
Diabetic Rats ◽  
Paraoxonase 1 ◽  
Matrix Metalloproteinase 2 ◽  
Altered Level ◽  
Neuropilin 1 ◽  
Coa Reductase

Advanced glycation end-products (AGEs) induce the production of reactive oxygen species (ROS) and extra cellular matrix (ECM) degradation via suppression of neuropilin-1 (NRP-1) and interaction with AGE-receptors (RAGE). This study aimed to reveal whether modulation of NRP-1 by rosuvastatin (RT) prevents AGE-induced renal injury via targeting RAGE/matrix metalloproteinase-2 (MMP-2) signaling in diabetic rats. Treatment with RT ameliorated the altered level of markers of glycemic control, renal injury, cholesterol, triglyceride (TG) and hepatic HMG-CoA reductase activity; the level of circulatory carboxymethyl-lysine (CML) and the accumulation of fluorogenic-AGEs in renal tissue was reduced; the expression of renal NRP-1, a checkpoint target, was stimulated; the transcription of RAGE, NF?B-2, TGF-?1 and MMP-2 was suppressed; the circulatory carbonyl content (CC) and paraoxonase-1 (PON-1) activity was ameliorated, and renal histopathological features were attenuated as evidenced by improved glomerular appearance, Bowman?s space and abundant podocytes in kidneys. In conclusion, RT exhibited the potential to counteract diabetes and AGE-induced renal pathologies via stimulation of NRP-1, suppression of RAGE, and of genes responsible for ECM disintegration (MMP-2) and the inflammatory response (NF?B-2).

scholarly journals Reduction of podocytes number in late diabetic alloxan nephropathy: prevention by glycemic control

2007 ◽  
Vol 22 (5) ◽  
pp. 337-341 ◽  
Author(s):  
Célia Sperandéo Macedo ◽  
Mauro Masson Lerco ◽  
Sônia Maria Capelletti ◽  
Reinaldo José Silva ◽  
Daniela de Oliveira Pinheiro ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Body Weight ◽  
Diabetic Nephropathy ◽  
Glycemic Control ◽  
Wistar Rats ◽  
Treated Group ◽  
Renal Tissue ◽  
Diabetic Rats ◽  
Gbm Thickening ◽  
Diabetes Induction

PURPOSE: To determine podocyte number and GBM thickness in diabetic rats either under glycemic control or without glycemic control at 6 and 12 months after diabetes induction. METHODS: 100 wistar rats weighing 200-300g were divided into 6 groups: Normal group (N6 and N12- 25 rats); Diabetic group (D6 and D12- 25 rats), diabetic treated group ( DT 6 and DT 12- 25 rats) on insulin 1,8- 3,0 IU/Kg associated with acarbose (50mg to 100g of food) daily mixed in chow. Alloxan was injected intravenously in a dose of 42 mg/Kg of weight. Body weight, waterintake, 24-h diuresis, glycemia and glucosuria were determined before induction, 7 and 14 days after induction and monthly thereafter. Treatment started at day 14. Three groups were sacrificed at 6 months (N6,D6, DT6) and 3 groups at 12 months (N12, D12, DT12) with the renal tissue being prepared for electron microscopy. RESULTS: Glycemia in DT6¨and in DT12 was significantly different from that in D6 and D12 rats and similar to that in N6 and N12 animals. The number of podocytes in DT6 was not different from that in N6 and D6 (median = 11); the number of podocytes in DT12 (median = 11) differed from that in D12 (median = 8), but not from that in N12 (median = 11). GBM thickness in D6 (0.18 micrometers) was lower than in D12 (0.29 micrometers); while in DT6 (0.16 micrometers) it was lower than in D6 (0.18 micrometers). In DT12 (0.26 micrometers), it was lower than in D12 (0.29 micrometers). CONCLUSION: The control of hyperglycemia prevented GBM thickening in early and late (12 mo) alloxan diabetic nephropathy and podocyte number reduction.

scholarly journals Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat

2012 ◽  
Vol 302 (3) ◽  
pp. F308-F315 ◽  
Author(s):  
Christine Maric-Bilkan ◽  
Elizabeth R. Flynn ◽  
Alejandro R. Chade
Keyword(s):  
Renal Function ◽  
Renal Injury ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Microvascular Disease ◽  
Renal Tissue ◽  
Diabetic Rat ◽  
Sprague Dawley ◽  
Micro Computed Tomography ◽  
Diabetic Kidney

Diabetic nephropathy is a progressive and generalized vasculopathic condition associated with abnormal angiogenesis. We aim to determine whether changes in renal microvascular (MV) density correlate with and play a role in the progressive deterioration of renal function in diabetes. We hypothesize that MV changes represent the early steps of renal injury that worsen as diabetes progresses, initiating a vicious circle that leads to irreversible renal injury. Male nondiabetic (ND) or streptozotocin-induced diabetic (D) Sprague-Dawley rats were followed for 4 or 12 wk. Renal blood flow and glomerular filtration rate (GFR) were measured by PAH and 125I-[iothalamate], respectively. Renal MV density was quantified ex vivo using three-dimensional micro computed tomography and JG-12 immunoreactivity. Vascular endothelial growth factor (VEGF) levels (ELISA) and expression of VEGF receptors and factors involved in MV remodeling were quantified in renal tissue by Western blotting. Finally, renal morphology was investigated by histology. Four weeks of diabetes was associated with increased GFR, accompanied by a 34% reduction in renal MV density and augmented renal VEGF levels. However, at 12 wk, while GFR remained similarly elevated, reduction of MV density was more pronounced (75%) and associated with increased MV remodeling, renal fibrosis, but unchanged renal VEGF compared with ND at 12 wk. The damage, loss, and subsequent remodeling of the renal MV architecture in the diabetic kidney may represent the initiating events of progressive renal injury. This study suggests a novel concept of MV disease as an early instigator of diabetic kidney disease that may precede and likely promote the decline in renal function.

MDM2 inhibition improves cisplatin-induced renal injury in mice via inactivation of Notch/hes1 signaling pathway

2020 ◽  
pp. 096032712095215
Author(s):  
X Luo ◽  
L Zhang ◽  
G-D Han ◽  
P Lu ◽  
Y Zhang
Keyword(s):  
Signaling Pathway ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Renal Tissue ◽  
Tunel Staining ◽  
Acute Renal Injury ◽  
Renal Tubular ◽  
Injury Models

Objective: To explore the potential function of MDM2-mediated Notch/hes1 signaling pathway in cisplatin-induced renal injury. Methods: The acute renal injury models of mice after intraperitoneal injection of cisplatin in vivo, and the apoptotic models of human renal tubular epithelial (HK-2) cells induced by cisplatin in vitro, were conducted respectively. The renal function-related parameters were measured. The renal tissue pathological changes and apoptosis were observed by PAS staining and TUNEL staining, respectively. Cell viability and apoptosis were detected by MTT and flow cytometry. Notch/hes1 pathway-related proteins were tested by Western blotting. Results: After mice injected by cisplatin, the levels of Cr, BUN, urine cystatin C, urine NGAL and urine ACR were increased and GFR was decreased with the elevation of renal tubular injury scores, the upregulation of the expressions of MDM2, N1ICD, Hes1 and Cleaved caspase-3, as well as the enhancement of cell apoptosis accompanying decreased ratio of Bcl-2/Bax. However, these cisplatin-induced renal injuries of mice have been improved by MDM2 inhibition. Besides, the declined viability, increased cytotoxicity, and enhanced apoptosis were observed in cisplatin-induced HK-2 cells, with the activated Notch/hes1 pathway. Notably, the phenomenon was alleviated in cisplatin-induced HK-2 cells transfected with MDM2 shRNA, but was severer in those co-treated with AdMDM2. Moreover, Notch1 siRNA can reverse the injury of AdMDM2 on HK-2 cells. Conclusion: Inhibiting MDM2 could reduce cell apoptosis through blocking Notch/hes1 signaling pathway, thus alleviating the acute renal injury caused by cisplatin.

scholarly journals Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy

Diabetes ◽  
2013 ◽  
Vol 63 (4) ◽  
pp. 1366-1380 ◽  
Author(s):  
L. Xiao ◽  
X. Zhu ◽  
S. Yang ◽  
F. Liu ◽  
Z. Zhou ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tubular Injury ◽  
Renal Tubular

scholarly journals Subcutaneous Transplantation of Islets into Streptozocin-Induced Diabetic Rats

2005 ◽  
Vol 14 (8) ◽  
pp. 595-605 ◽  
Author(s):  
Craig R. Halberstadt ◽  
Deana Williams ◽  
Dwaine Emerich ◽  
Moses Goddard ◽  
Alfred V. Vasconcellos ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Cell Function ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Pancreatic Islet Transplantation ◽  
Minimally Invasive Surgical Procedure ◽  
Minimally Invasive Surgical ◽  
Ease Of Access ◽  
Syngeneic Islet Transplantation ◽  
Type 1 Diabetic Patients

Pancreatic islet transplantation into type 1 diabetic patients is currently being performed by intraportal infusion. This method, albeit reproducible, has some disadvantages including potential development of portal hypertension, hemorrhage, and an inability to retrieve or detect the transplanted tissue. Other transplant sites have been examined in animal models including the omentum, peritoneal cavity, and the spleen. A transplant site that has not been successful in supporting functional islet tissue transplantation in humans is the subcutaneous space due primarily to the lack of a well-defined vascular bed. This site has many favorable characteristics such as ease of access for transplantation and potential for removal of the transplanted tissue with a minimally invasive surgical procedure. This report addresses the evaluation of a subcutaneously placed device for the support of rat syngeneic islet transplantation in a streptozocin-induced diabetic model. The data generated support the use of this device for islet engraftment. In addition, beta cell function in this device compared favorably with the function of islets transplanted to the renal subcapsular space as well as islets within the native pancreas.

scholarly journals ADAMTS13/VWF Axis Potentially Contributes to Diabetic Nephropathy By Regulating PAI-1 Levels

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2240-2240
Author(s):  
Nirav Dhanesha ◽  
Anil K. Chauhan
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Weight Ratio ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Body Weight Ratio ◽  
Renal Hypertrophy ◽  
Protein Levels ◽  
Pai 1

Abstract Background and objective: ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13) cleaves von Willebrand factor (VWF), a large multimeric protein that plays an important role in hemostasis and thrombosis. Severe deficiency or very low levels of ADAMTS13 in presence of external stimuli results in accumulation of thrombogenic ultra large VWF multimers (which are released from activated endothelium) known to trigger thrombotic microangiopathy. Activated endothelium/dysfunction is a prominent feature of diabetic nephropathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy. Significantly reduced ADAMTS13 and increased plasma VWF levels have been found in diabetic patients with nephropathy. Although major site of ADAMTS13 synthesis is liver, ADAMTS13 is also expressed by podocytes in normal renal cortex. It remains unknown, however, whether VWF and ADAMTS13 imbalance plays a causal role in development of nephropathy in diabetic patients or rather is simply an associate marker of disease status, possibly secondary to endothelial function. We performed experiments in genetic models to determine whether ADAMTS13 and VWF axis contributes to diabetic nephropathy. Methods : Male, 8-10 weeks old wild-type (WT), Adamts13-/- and Vwf-/- mice were made diabetic by injecting multiple low doses of streptozotocin (60 mg/kg, i.p. for five consecutive days). Successful diabetes induction was tested after 2 weeks by measuring blood glucose. Mice having blood glucose levels above 300 mg/dL were included in the study. Controls were nondiabetic littermate mice treated with citrate buffer. The extent of renal injury was evaluated after 28 weeks of diabetes induction by measuring albuminuria and kidney to body weight ratio. Renal hypertrophy and extracellular matrix deposition was quantified by hematoxylin and immunostaining. PAI-1 mRNA and protein levels were measured by real time quantitative RT-PCR and ELISA. Results: Adamts13- /- diabetic mice exhibited significantly increased kidney to body weight ratio (P<0.05 vs. WT diabetic mice). Urine albuminuria, an index of renal injury was significantly elevated in Adamts13-/- diabetic mice (P<0.05 vs. WT diabetic mice). Increased renal injury in Adamts13-/- diabetic mice was concomitant with increased renal hypertrophy and extracellular matrix (ECM) deposition within glomeruli (P<0.05 vs. WT diabetic mice). Murine studies have shown that PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and ECM deposition. A positive association exists between increased PAI-1 levels in glomeruli and microangiopathy in patients with diabetic nephropathy. We determined whether ADAMTS13 deficiency-induced microangiopathy in glomeruli increases PAI-1 levels. Adamts13-/- diabetic mice exhibited increased PAI-1 mRNA and protein levels (P<0.05 vs. WT diabetic mice). VWF remains the only known substrate of ADAMTS13 and increased plasma VWF levels have been associated with diabetic nephropathy. We determined the role of VWF in diabetic nephropathy. Vwf-/- diabetic mice exhibited significantly decreased kidney weight/body weight ratio, less urinary albuminuria, decreased kidney PAI-1 expression levels concomitant with improved kidney morphological changes (P<0.05 vs. WT diabetic mice). Conclusion : These findings provide experimental evidence for the first time that ADAMTS13/VWF axis potentially contributes to diabetic nephropathy, most likely by regulating PAI-1 levels. Disclosures No relevant conflicts of interest to declare.

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