scholarly journals Protective Effect of Yi Shen Pai Du Formula against Diabetic Kidney Injury via Inhibition of Oxidative Stress, Inflammation, and Epithelial-to-Mesenchymal Transition in db/db Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Qilin Zhang ◽  
Xiaocui Liu ◽  
Mitchell A. Sullivan ◽  
Chen Shi ◽  
Bin Deng
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Nlrp3 Inflammasome ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Model ◽  
Microvascular Complications ◽  
Fasting Blood Glucose ◽  
Diabetic Kidney ◽  
Mesenchymal Transition ◽  
Caspase 1

Objective. Diabetic kidney disease (DKD) is one of the most common chronic microvascular complications of diabetes; however, there remains a lack of effective therapeutic strategies. Yi Shen Pai Du Formula (YSPDF), a traditional Chinese medicine preparation, has been clinically used in treating chronic kidney disease (CKD) for more than 20 years. However, whether YSPDF has a therapeutic effect on DKD has not been studied. Methods. This study was conducted to investigate the effect of YSPDF administration on db/db mice, a model of type 2 diabetes that develops DKD, and reveal its underlying mechanism of action through a high glucose- (HG-) induced renal injury cell model. Results. We found that YSPDF significantly improved numerous biochemical parameters (fasting blood glucose, serum creatinine, blood urea nitrogen, 24 h urine total protein, total cholesterol, and total triglycerides) and ameliorated the abnormal histology and fibrosis of renal tissue. Moreover, the status of oxidative stress and levels of inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1) were markedly inhibited by YSPDF treatment. YSPDF treatment significantly mitigated renal fibrosis, with evidence suggesting that this was by inhibiting epithelial-to-mesenchymal transition (EMT) via suppression of the TGF-β1/Smad pathway. Interestingly, the expression of Nrf2, HO-1, and NQO1, proteins known to be associated with oxidative stress, were significantly increased upon administration of YSPDF. The levels of NLRP3 inflammasome proteins, including NLRP3, ASC, caspase-1, and cleaved caspase-1 were decreased in the YSPDF-treated group. Cell experiments showed that YSPDF inhibited EMT and the NLRP3 inflammasome in HG-exposed HK-2 cells, possibly via activation of Nrf2. Conclusion. Our study indicates that YSPDF may ameliorate renal damage in db/db mice via inhibition of oxidative stress, inflammation, and EMT, with the mechanism potentially being related to the activation of the Nrf2 pathway.

scholarly journals Effects of ZnT8 on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis in diabetic kidney disease

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Xiuli Zhang ◽  
Tingwen Guan ◽  
Boxuan Yang ◽  
Harvest F. Gu ◽  
Zhihong Chi
Keyword(s):  
Kidney Disease ◽  
Pancreatic Beta Cells ◽  
Diabetic Kidney Disease ◽  
Epithelial To Mesenchymal Transition ◽  
Gene Transfection ◽  
Tubulointerstitial Fibrosis ◽  
Inflammatory Factors ◽  
Diabetic Kidney ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Zinc transporter 8 (ZnT8) transports zinc ions for crystallization and storage of insulin in pancreatic beta-cells and ZnT8 dysfunction is involved in pathogenesis of diabetes. The current study aimed to investigate whether ZnT8 has effects in pathophysiology of diabetic kidney disease (DKD) by using animal models for diabetes, including STZ-induced diabetic, db/db, ZnT8-KO, ZnT8-KO-STZ and ZnT8-KO-db/db mice. Results demonstrated that urine albumin to creatinine ratio and epithelial-to-mesenchymal transition (EMT) were increased in kidneys of ZnT8-KO-STZ and ZnT8-KO-db/db mice compared with C57BL/6 J and ZnT8-KO mice, while serum TGF-β1, IL-6, and TNF-α levels were elevated in parallel. In kidneys of mice intercrossed between ZnT8-KO and STZ-induced diabetic or db/db mice, these three inflammatory factors, ACR and EMT were also found to be increased compared with C57BL/6J, db/db and ZnT8-KO mice. Furthermore, ZnT8 up-regulation by hZnT8-EGFP reduced the levels of high glucose (HG)-induced EMT and inflammatory factors in normal rat kidney tubular epithelial cell (NRK-52E cells). Expression of phosphorylated Smad2/Smad3 was up-regulated after HG stimulation and further enhanced by ZnT8 siRNA but down-regulated after hZnT8-EGFP gene transfection. The current study thus provides the first evidence that ZnT8 protects against EMT-tubulointerstitial fibrosis though the restrain of TGF-β1/Smads signaling activation in DKD.

scholarly journals XOR - Possible Correlations with Oxidative Stress and Inflammation Markers in the Context of Diabetic Kidney Disease

2019 ◽  
Vol 70 (4) ◽  
pp. 1396-1398 ◽  
Author(s):  
Alexandra Totan ◽  
Andra-Elena Balcangiu-Stroescu ◽  
Marina Melescanu Imre ◽  
Daniela Miricescu ◽  
Daniela Balan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Microvascular Complications ◽  
Serum Levels ◽  
Control Group ◽  
Diabetic Patients ◽  
Inflammation Markers ◽  
Diabetic Kidney ◽  
Diabetic Microvascular Complications

Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species. The aim of our study was to investigate possible correlations of XOR serum levels with oxidative stress (total antioxidant capacity - TAC, anti-oxidative stress responsive 1 antibody - OXSR1) and inflammation markers (interleukin 6 - IL-6), in 20 hemodialysis diabetic patients. The present study included the hemodialysis diabetic patients group (10 males and 10 females) and the control group (20 healthy volunteers). For serum XOR (ng/mL), TAC (U/mL) and OXSR1 (ng/ml) measurements we have used the ELISA technique. Serum IL6 (pg/mL) was performed using an automatic immunoassay system (Immulite 1000, Siemens- Germany). Comparing the two groups, our results revealed significantly increased serum levels for XOR (6.2�1.5 / 3.9�1.1); OXSR1 (11.3�2.9 / 6.2�2.1) and IL6 (7.0�1.2 / 5.0�0.4). Patients� serum levels of TAC were significantly decreased compared with the control group values (25.2�3.9 / 33.5�2.8). It becomes more and more obvious that oxidative stress is an important element initiating diabetic microvascular complications, including diabetic kidney disease. Our results suggested that XOR should be regarded as an important target in the attempt to reduce oxidative stress in the context of diabetic kidney disease.

scholarly journals Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1143
Author(s):  
Midori Sakashita ◽  
Tetsuhiro Tanaka ◽  
Reiko Inagi
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Stress Responses ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Therapeutic Agents ◽  
Metabolic Changes ◽  
Diabetic Kidney ◽  
Glucose Levels ◽  
Patients With Diabetes

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

N6 -(2-hydroxyethyl)-adenosine from Cordyceps cicadae protects against diabetic kidney disease via alleviation of oxidative stress and inflammation

2018 ◽  
Vol 43 (2) ◽  
pp. e12727 ◽  
Author(s):  
Xiaohong Wang ◽  
Aiqiong Qin ◽  
Fang Xiao ◽  
Opeyemi J. Olatunji ◽  
Shuyuan Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Cordyceps Cicadae

scholarly journals Sulodexide Protects Renal Tubular Epithelial Cells from Oxidative Stress-Induced Injury via Upregulating Klotho Expression at an Early Stage of Diabetic Kidney Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Yu Ning Liu ◽  
Jingwei Zhou ◽  
Tingting Li ◽  
Jing Wu ◽  
Shu Hua Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Epithelial Cells ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Collaborative Study ◽  
Oxidative Activity ◽  
Dependent Manner ◽  
Diabetic Kidney ◽  
Collaborative Study Group

The hypoalbuminuric effect of sulodexide (SDX) on diabetic kidney disease (DKD) was suggested by some clinical trials but was denied by the Collaborative Study Group. In this study, the diabetic rats were treated with SDX either from week 0 to 24 or from week 13 to 24. We found that 24-week treatment significantly decreased the urinary protein and HAVCR1 excretion, inhibited the interstitial expansion, and downregulated the renal cell apoptosis and interstitial fibrosis. Renoprotection was also associated with a reduction in renocortical/urinary oxidative activity and the normalization of renal klotho expression. However, all of these actions were not observed when SDX was administered only at the late stage of diabetic nephropathy (from week 13 to 24). In vitro, advanced glycation end products (AGEs) dose-dependently enhanced the oxidative activity but lowered the klotho expression in cultured proximal tubule epithelial cells (PTECs). Also, H2O2 could downregulate the expression of klotho in a dose-dependent manner. However, overexpression of klotho reduced the HAVCR1 production and the cellular apoptosis level induced by AGEs or H2O2. Our study suggests that SDX may prevent the progression of DKD at the early stage by upregulating renal klotho expression, which inhibits the tubulointerstitial injury induced by oxidative stress.

Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease

2011 ◽  
Vol 300 (2) ◽  
pp. F511-F520 ◽  
Author(s):  
Hiroko Togawa ◽  
Koichi Nakanishi ◽  
Hironobu Mukaiyama ◽  
Taketsugu Hama ◽  
Yuko Shima ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Contact ◽  
Polycystic Kidney ◽  
Mesenchymal Transition ◽  
Cyst Lining ◽  
E Cadherin

In polycystic kidney disease (PKD), cyst lining cells show polarity abnormalities. Recent studies have demonstrated loss of cell contact in cyst cells, suggesting induction of epithelial-to-mesenchymal transition (EMT). Recently, EMT has been implicated in the pathogenesis of PKD. To explore further evidence of EMT in PKD, we examined age- and segment-specific expression of adhesion molecules and mesenchymal markers in PCK rats, an orthologous model of human autosomal-recessive PKD. Kidneys from 5 male PCK and 5 control rats each at 0 days, 1, 3, 10, and 14 wk, and 4 mo of age were serially sectioned and stained with segment-specific markers and antibodies against E-cadherin, Snail1, β-catenin, and N-cadherin. mRNAs for E-cadherin and Snail1 were quantified by real-time PCR. Vimentin, fibronectin, and α-smooth muscle actin (α-SMA) expressions were assessed as mesenchymal markers. E-cadherin expression pattern was correlated with the disease pathology in that tubule segments showing the highest expression in control had much severer cyst formation in PCK rats. In PCK rats, E-cadherin and β-catenin in cystic tubules was attenuated and localized to lateral areas of cell-cell contact, whereas nuclear expression of Snail1 increased in parallel with cyst enlargement. Some epithelial cells in large cysts derived from these segments, especially in adjacent fibrotic areas, showed positive immunoreactivity for vimentin and fibronectin. In conclusion, these findings suggest that epithelial cells in cysts acquire mesenchymal features in response to cyst enlargement and participate in progressive renal fibrosis. Our study clarified the nephron segment-specific cyst profile related to EMT in PCK rats. EMT may play a key role in polycystic kidney disease.

scholarly journals Diabetic Kidney Disease in Childhood and Adolescence: Conventional and Novel Renoprotective Strategies

2020 ◽  
pp. 68-77
Author(s):  
Samuel N Uwaezuoke ◽  
Adaeze C Ayuk
Keyword(s):  
Diabetes Mellitus ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Microvascular Complications ◽  
Clinical Syndrome ◽  
Clinical Staging ◽  
Childhood And Adolescence ◽  
Diabetic Kidney ◽  
Haemodynamic Changes ◽  
End Stage

Diabetic kidney disease (DKD) is defined as a clinical syndrome consisting of persistent macroalbuminuria, progressive decline in glomerular filtration rate (GFR), hypertension, increased cardiovascular disease events, and the associated mortality of these conditions. The disease evolves from the microvascular complications of poorly controlled Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). The pathogenic pathways comprise renal haemodynamic changes, ischaemia and inflammation, and overactive renin–angiotensin–aldosterone system (RAAS), through which several events cascade down from hyperglycaemia to renal fibrosis. Conventional and novel renoprotective strategies target modifiable DKD risk factors and specific stages of the pathogenic pathways, respectively. Although these strategies may slow DKD progression to end-stage kidney disease (ESKD), novel drugs are still undergoing trials for validation in human participants. This narrative review appraises these renoprotective strategies and highlights the current clinical staging and pathogenesis of the disease.

scholarly journals Loss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease

Diabetes ◽  
2021 ◽  
pp. db210316
Author(s):  
Nehaben A. Gujarati ◽  
Alexandra R. Leonardo ◽  
Jessica M. Vasquez ◽  
Yiqing Guo ◽  
Bismark O. Frimpong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney

scholarly journals Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

2021 ◽  
Vol 22 (19) ◽  
pp. 10822
Author(s):  
Agata Winiarska ◽  
Monika Knysak ◽  
Katarzyna Nabrdalik ◽  
Janusz Gumprecht ◽  
Tomasz Stompór
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Organ Protection ◽  
In Vivo Models ◽  
Diabetic Kidney ◽  
And Oxidative Stress

The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

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