Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy

2012 ◽  
Vol 302 (6) ◽  
pp. F647-F657 ◽  
Author(s):  
Maria-Dolores Sanchez-Niño ◽  
Milica Bozic ◽  
Elizabeth Córdoba-Lanús ◽  
Petya Valcheva ◽  
Olga Gracia ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Mrna Expression ◽  
Experimental Model ◽  
High Glucose ◽  
Glomerular Cell ◽  
Renal Inflammation ◽  
Matrix Deposition ◽  
Mediators Of Inflammation ◽  
Anti Inflammatory

Local inflammation is thought to contribute to the progression of diabetic nephropathy. The vitamin D receptor (VDR) activator paricalcitol has an antiproteinuric effect in human diabetic nephropathy at high doses. We have explored potential anti-inflammatory effects of VDR activator doses that do not modulate proteinuria in an experimental model of diabetic nephropathy to gain insights into potential benefits of VDR activators in those patients whose proteinuria is not decreased by this therapy. The effect of calcitriol and paricalcitol on renal function, albuminuria, and renal inflammation was explored in a rat experimental model of diabetes induced by streptozotocin. Modulation of the expression of mediators of inflammation by these drugs was explored in cultured podocytes. At the doses used, neither calcitriol nor paricalcitol significantly modified renal function or reduced albuminuria in experimental diabetes. However, both drugs reduced the total kidney mRNA expression of IL-6, monocyte chemoattractant protein (MCP)-1, and IL-18. Immunohistochemistry showed that calcitriol and paricalcitol reduced MCP-1 and IL-6 in podocytes and tubular cells as well as glomerular infiltration by macrophages, glomerular cell NF-κB activation, apoptosis, and extracellular matrix deposition. In cultured podocytes, paricalcitol and calcitriol at concentrations in the physiological and clinically significant range prevented the increase in MCP-1, IL-6, renin, and fibronectin mRNA expression and the secretion of MCP-1 to the culture media induced by high glucose. In conclusion, in experimental diabetic nephropathy VDR activation has local renal anti-inflammatory effects that can be observed even when proteinuria is not decreased. This may be ascribed to decreased inflammatory responses of intrinsic renal cells, including podocytes, to high glucose.

scholarly journals Buyang Huanwu Decoction protects against STZ-induced diabetic nephropathy by inhibiting TGF-β/Smad3 signaling-mediated renal fibrosis and inflammation

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Weifeng Wu ◽  
Yifan Wang ◽  
Haidi Li ◽  
Haiyong Chen ◽  
Jiangang Shen
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Renal Fibrosis ◽  
Mesangial Cells ◽  
Buyang Huanwu Decoction ◽  
Active Compounds ◽  
Renal Inflammation ◽  
Pas Staining ◽  
Tgf Β1

Abstract Background Buyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD. Methods Mice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms. Results We found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells. Conclusion BHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy.

scholarly journals Adenosine A1 Receptor Deficiency Aggravates Extracellular Matrix Accumulation in Diabetic Nephropathy through Disturbance of Peritubular Microenvironment

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Dongli Tian ◽  
Jiaying Li ◽  
Linfeng Zou ◽  
Min Lin ◽  
Xiaoxiao Shi ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Immunohistochemical Staining ◽  
Adenosine A1 Receptor ◽  
Pronounced Increase ◽  
Matrix Deposition ◽  
Adenosine A1 ◽  
Proximal Tubular ◽  
A1 Receptor

Background. We previously observed that adenosine A1 receptor (A1AR) had a protective role in proximal tubular megalin loss associated with albuminuria in diabetic nephropathy (DN). In this study, we aimed to explore the role of A1AR in the fibrosis progression of DN. Methods. We collected DN patients’ samples and established a streptozotocin-induced diabetes model in wild-type (WT) and A1AR-deficient (A1AR-/-) mice. The location and expression of CD34, PDGFRβ, and A1AR were detected in kidney tissue samples from DN patients by immunofluorescent and immunohistochemical staining. We also analyzed the expression of TGFβ, collagen (I, III, and IV), α-SMA, and PDGFRβ using immunohistochemistry in WT and A1AR-/- mice. CD34 and podoplanin expression were analyzed by Western blotting and immunohistochemical staining in mice, respectively. Human renal proximal tubular epithelial cells (HK2) were cultured in medium containing high glucose and A1AR agonist as well as antagonist. Results. In DN patients, the expression of PDGFRβ was higher with the loss of CD34. The location of PDGFRβ and TGFβ was near to each other. The A1AR, which was colocalized with CD34 partly, was also upregulated in DN patients. In WT-DN mice, obvious albuminuria and renal pathological leisure were observed. In A1AR-/- DN mice, more severe renal tubular interstitial fibrosis and more extracellular matrix deposition were observed, with lower CD34 expression and pronounced increase of PDGFRβ. In HK2 cells, high glucose stimulated the epithelial-mesenchymal transition (EMT) process, which was inhibited by A1AR agonist. Conclusion. A1AR played a critical role in protecting the tubulointerstitial fibrosis process in DN by regulation of the peritubular microenvironment.

P0672CALPAINS 1 AND 2 ARE INCREASED DURING THE DEVELOPMENT OF CHRONIC KIDNEY DAMAGE IN MICE FED WITH AN ADENINE RICH DIET

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Elena Gutiérrez-Calabrés ◽  
Sofía Campillo de Blas ◽  
Lourdes Bohorquez Magro ◽  
Mercedes Griera-Merino ◽  
Diego García Ayuso ◽  
...  
Keyword(s):  
Renal Function ◽  
Mrna Expression ◽  
Protein Content ◽  
Experimental Model ◽  
Collagen Type ◽  
Critical Role ◽  
Cysteine Proteases ◽  
Collagen Type I ◽  
Standard Diet ◽  
Type I

Abstract Background and Aims Calpains are intracellular cysteine proteases that play a critical role in cell remodeling, being involved in multiple biological processes linked to tissue damage and repair mechanisms. In addition, they are released into the circulation, being able to carry out systemic actions with pathological consequences. The aim of this study was to investigate the role of calpains in the progression of chronic kidney disease (CKD) in an experimental model of chronic renal damage induced by adenine. Method We induced an experimental model of CKD, in mice fed for 2 weeks with an adenine-supplemented diet (0.2% adenine) (A). Animals receiving this diet develop a tubulointerstitial damage resembling that is observed in human CKD. Mice with standard diet were used as controls (C). Renal function was assessed by measuring serum blood urea nitrogen (BUN) and creatinine (mg/dl). Fibrosis markers (collagen type I and fibronectin) were determined by RT-qPCR. Changes in the renal content of calpains 1 and 2 were analyzed by western blot (protein content), and RT-qPCR (mRNA expression). Results Our results show functional and structural changes at renal level in the adenine-fed mice, with increased BUN (A: 72 mg/dl, C: 28 mg/dl, p < 0.05), creatinine (A: 0.58 mg/dl, C: 0.25 mg/dl, p < 0.05), collagen type I mRNA expression (A: 12.9 units, C: 1.2 units, p < 0.05) and fibronectin mRNA expression (A: 3.46 units, C: 1.3 units, p < 0.05). Furthermore, protein content of calpains 1 (A: 1.27 units, C: 0.78 units, p < 0.05) and 2 (A: 1.30 units, C: 0.66 units, p < 0.05) was significantly higher in adenine-fed mice when compared to control. At the same time, we observed a significant increase in gene expression of both calpain 1 (A: 4.21 units, C: 0.51 units, p < 0.05) and 2 (A: 4.93 units, C: 0.56 units, p < 0.05) in the adenine model regarding to mice with standard diet. Our results demonstrate that calpain 1 and 2 expression in renal tissue increases as CKD progresses. Interestingly, we found statistically significant correlations between renal calpains 1 and 2 protein and mRNA content and plasma BUN and creatinine (p < 0.05, r between 0.79 and 0.92), as well as protein expression of calpain 2 and mRNA expression of collagen type I (p < 0.05, r = 0.76). These data suggest a potential direct relationship between renal calpain 1 and 2 content and loss of renal function, in part due probably to the modulation of the fibrotic changes, in adenine fed mice. Conclusion We suggest an implication of calpains 1 and 2 in the development of CKD. Thus, effective calpain blockade or downregulation could be useful as a therapeutic strategy to prevent CKD. Further experiments will be necessary to establish the relationship between these factors.

scholarly journals Effects of HuoxueJiangtang decoction alone or in combination with metformin on renal function and renal cortical mRNA expression in diabetic nephropathy rats

2020 ◽  
Vol 58 (1) ◽  
pp. 1123-1130
Author(s):  
Xuemei Liu ◽  
Deliang Liu ◽  
Youyou Shuai ◽  
Huilin Li ◽  
Hengxia Zhao ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Mrna Expression

scholarly journals The cyclin kinase inhibitor p21WAF1, CIP1 is increased in experimental diabetic nephropathy: potential role in glomerular hypertrophy.

1998 ◽  
Vol 9 (6) ◽  
pp. 986-993 ◽  
Author(s):  
C J Kuan ◽  
M al-Douahji ◽  
S J Shankland
Keyword(s):  
Cell Cycle ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Mesangial Cell ◽  
Kinase Inhibitor ◽  
Glomerular Hypertrophy ◽  
Glomerular Cell ◽  
Cyclin Dependent Kinases ◽  
Cell Hypertrophy

High glucose inhibits mesangial cell proliferation in vitro and induces hypertrophy in mesangial cells in culture and in experimental diabetic nephropathy. Cell growth is ultimately controlled at the level of the cell cycle by cell cycle regulatory proteins. Cell cycle progression requires that cyclin-dependent kinases be activated by cyclins. Cyclin kinase inhibitors (CKI) inactivate cyclin-dependent kinases, causing cell cycle arrest. In the current study, high glucose-induced mesangial cell hypertrophy in vitro is shown to be associated with increased levels of the CKI p21, but not p27. In the streptozotocin model of experimental diabetes in the mouse, glomerular hypertrophy was associated with a selective increase in p21 expression, whereas the levels of the CKI p27 and p57 did not change. Unlike many other forms of glomerular injury, diabetic nephropathy was not associated with increased apoptosis. These results support a role for p21 in causing glomerular cell hypertrophy in diabetic nephropathy.

scholarly journals ATRvD1 Attenuates Renal Tubulointerstitial Injury Induced by Albumin Overload in Sepsis-Surviving Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11634
Author(s):  
José Bruno N. F. Silva ◽  
Thayanne B. B. Calcia ◽  
Cyntia P. Silva ◽  
Rafael F. Guilherme ◽  
Fernando Almeida-Souza ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Animal Model ◽  
Mrna Expression ◽  
Transforming Growth Factor ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Tubulointerstitial Injury ◽  
Glomerular Cell ◽  
Matrix Deposition

Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor β (TGFβ), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1+ cells. The interleukin-1β (IL-1β) levels were increased in the subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-α (TNF-α), IL-10, and IL-4 mRNA expression were increased in the kidney of BSA-challenged post-septic mice, and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult such as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.

scholarly journals Proteasome subunit-α type-6 protein is post-transcriptionally repressed by the microRNA-4490 in diabetic nephropathy

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Ying Feng ◽  
Ming-yue Jin ◽  
Dong-wei Liu ◽  
Li Wei
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Expression ◽  
Mrna Expression ◽  
High Glucose ◽  
Renal Cortex ◽  
Luciferase Assay ◽  
Diabetic Patients ◽  
Proteasome Subunit ◽  
High Glucose Condition ◽  
Glucose Condition

A common complication of both type I and type II diabetes is nephropathy, characterized by accumulation of extracellular matrix in the glomerular mesangium. This indicates a central role of mesangial cells in the pathophysiology of diabetic nephropathy. Using the proteomic approach, it was earlier elucidated in a rat model that the proteasome subunit-α type-6 protein (PSMA6) is suppressed in the renal cortex in nephropathic kidney. However, the underlying mechanism effecting suppression of PSMA6 protein in the renal cortex is not yet known. Twenty diabetic patients were enrolled and the expression level of PSMA6 in them was detected by immunohistochemistry. The protein and mRNA expression levels of PSMA6 in NRK-52E cells under high glucose condition were determined by Western blot and quantitative real-time PCR, respectively. Dual luciferase assay was used to detect the relationship of PSMA6 and miR-4490. Our results show that PSMA6 protein is down-regulated in patients with diabetic nephropathy compared with healthy control. Using the NRK-52E cell line cultured under high glucose condition as an in vitro model of diabetic nephropathy, we show that loss of PSMA6 protein expression occured independent of changes the in PSMA6 mRNA expression. We next elucidate that PSMA6 mRNA is post-transcriptionally regulated by the microRNA (miRNA)-4490, whose expression is inversely correlated to PSMA6 protein expression. Using reporter assays we show that PSMA6 is a direct target of the miR-4490. Exogenous manipulation of miR-4490 levels modulated expression of PSMA6, indicating that miR-4490 can be tested as a biomarker for nephropathy in diabetic patients.

scholarly journals Carpinus turczaninowii Extract May Alleviate High Glucose-Induced Arterial Damage and Inflammation

Antioxidants ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 172 ◽  
Author(s):  
Juhyun Song ◽  
So Ra Yoon ◽  
Youn Kyoung Son ◽  
Woo Young Bang ◽  
Chang-Hwan Bae ◽  
...  
Keyword(s):  
Mrna Expression ◽  
High Glucose ◽  
Adenosine Monophosphate ◽  
Ultra Performance Liquid Chromatography ◽  
Response To Treatment ◽  
Proinflammatory Response ◽  
Expression Levels ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Arterial Damage

Hyperglycemia-induced oxidative stress triggers severe vascular damage and induces an inflammatory vascular state, and is, therefore, one of the main causes of atherosclerosis. Recently, interest in the natural compound Carpinus turczaninowii has increased because of its reported antioxidant and anti-inflammatory properties. We investigated whether a C. turczaninowii extract was capable of attenuating high glucose-induced inflammation and arterial damage using human aortic vascular smooth muscle cells (hASMCs). mRNA expression levels of proinflammatory response [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)], endoplasmic reticulum (ER) stress [CCAAT-enhancer-binding proteins (C/EBP) homologous protein (CHOP)], and adenosine monophosphate (AMP)-protein activated kinase α2 (AMPK α2)], and DNA damage [phosphorylated H2.AX (p-H2.AX)] were measured in hASMCs treated with the C. turczaninowii extracts (1 and 10 μg/mL) after being stimulated by high glucose (25 mM) or not. The C. turczaninowii extract attenuated the increased mRNA expression of IL-6, TNF-α, and CHOP in hASMCs under high glucose conditions. The expression levels of p-H2.AX and AMPK α2 induced by high glucose were also significantly decreased in response to treatment with the C. turczaninowii extract. In addition, 15 types of phenolic compounds including quercetin, myricitrin, and ellagic acid, which exhibit antioxidant and anti-inflammatory properties, were identified in the C. turczaninowii extract through ultra-performance liquid chromatography-quadrupole-time of flight (UPLC-Q-TOF) mass spectrometry. In conclusion, C. turczaninowii may alleviate high glucose-induced inflammation and arterial damage in hASMCs, and may have potential in the treatment of hyperglycemia-induced atherosclerosis.

scholarly journals ATRvD1 Attenuates Renal Tubulointerstitial Injury Induced by Albumin Overload in Sepsis-Surviving Mice

2021 ◽  
Author(s):  
José Bruno N. F. Silva ◽  
Thayanne B. B. Calcia ◽  
Cyntia P. Silva ◽  
Rafael F. Guilherme ◽  
Fernando Almeida-Souza ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Animal Model ◽  
Mrna Expression ◽  
Transforming Growth Factor ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Tubulointerstitial Injury ◽  
Glomerular Cell ◽  
Matrix Deposition

Current interventions are not effectives in preventing sepsis-induced acute kidney injury and its long-term outcomes or even after second renal insult. Therapeutic strategies using lipid mediators, as aspirin-triggered resolvin D1 (ATRvD1), can contribute for resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing the proteinuria excretion, UPC ratio, glomerular cell number and extracellular matrix deposition. Pro-fibrotic markers, as transforming growth factor β (TGFb), type 3 collagen and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from renal apoptosis and recruitment of F4/80+ cells. Interleukin-1b (IL-1b) levels were increased in subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-a (TNF-a), IL-10 and IL-4 mRNA expression was increased in the kidney of BSA-challenged post-septic mice and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.

Sign in / Sign up

Export Citation Format

Share Document