Anti‐Diabetic Agent Sodium Tungstate Induces the Secretion of Pro‐ and Anti‐Inflammatory Cytokines by Human Kidney Cells

Bertinat, Romina; Westermeier, Francisco; Silva, Pamela; Shi, Jihong; Nualart, Francisco; Li, Xuhang; Yáñez, Alejandro J.

doi:10.1002/jcp.25429

Cited by 11 publications

(9 citation statements)

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“…In addition to angiogenesis, microinflammation plays an important role in the development and progression of DKD [34][35][36][37][38]. Both intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been found to be upregulated in DKD; as suggested by their names, these two factors facilitate the adhesion of inflammatory cells and recruit circulating immune cells [39,40].…”

Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

Zhou¹,

Chen²,

Li³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. However, no effective treatments for this disease are available. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. DKD and retinopathy often co-exist and have similar mechanisms of pathogenesis. The aim of the present study was to elucidate the safety and efficacy of CaD in the treatment of DKD. Methods: In the prospective randomised controlled study, 100 DKD from Type 2 diabetes mellitus (DM) patients with a urinary albumin/ creatinine ratio (ACR) ≥30 mg/g and urinary protein level between 150 mg/24 h and 2 g/24 h with GFR> 90ml/min were enrolled. The patients were randomly divided into the treatment group (500 mg of CaD, administered orally, 3 times per day) and the control group. DKD patients were treated for 3 months. In the case control study, DM patients without proteinuria and healthy individuals were also enrolled. Clinical data and related biochemical parameters were collected. Endothelial function markers (VEGF, ET-1, eNOS, NO) and inflammatory markers (MCP-1, ICAM, PTX3) were detected by ELISA. Results: In the prospective randomised controlled study, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased after three months of treatment with CaD in the patients with DKD, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, ET-1) were significantly reduced compared to pre-treatment levels, NO was signifcantly increased post treatment. In the case control study, we found that PTX3, MCP-1, ICAM, VEGF and ET-1 levels were positively correlated with urinary albumin in DKD patients, while the NO level was negatively correlated. Logistic regression analysis showed that PTX3, NO and HbAlc were influential factors in DKD. After patients with DKD were treated with CaD for three months, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, NO, ET-1) were significantly reduced compared to pre-treatment levels. Conclusion: CaD can be safely and effectively used to treatdiabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

Zhou¹,

Chen²,

Li³

et al. 2018

Cell Physiol Biochem

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“…In the present work, we observed that PEPCK immunostaining was severely reduced only in those cortical proximal tubules affected by glycogenic alteration in NaW-IRS2-KO mice. It has been reported that NaW, as an insulin-mimetic agent, downregulates PEPCK expression in the liver from WT diabetic rats [ 22 ] and in human proximal tubules in vitro [ 23 ]. However, previous findings described an inconsistent effect of NaW in downregulating PEPCK in the liver from IRS2-KO mice [ 4 ], suggesting that IRS2 expression is required.…”

Section: Discussionmentioning

confidence: 99%

The Antidiabetic Agent Sodium Tungstate Induces Abnormal Glycogen Accumulation in Renal Proximal Tubules from Diabetic IRS2-Knockout Mice

Bertinat

Westermeier

Silva

et al. 2018

Journal of Diabetes Research

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The kidney is an insulin-sensitive organ involved in glucose homeostasis. One major effect of insulin is to induce glycogen storage in the liver and muscle. However, no significant glycogen stores are detected in normal kidneys, but diabetic subjects present a characteristic renal histopathological feature resulting from extensive glycogen deposition mostly in nonproximal tubules. The mechanism of renal glycogen accumulation is yet poorly understood. Here, we studied in situ glycogen accumulation in the kidney from diabetic IRS2-knockout mice and the effect of the insulin-mimetic agent sodium tungstate (NaW). IRS2-knockout mice displayed hyperglycemia and hyperinsulinemia. NaW only normalized glycemia. There was no evident morphological difference between kidneys from untreated wild-type (WT), NaW-treated WT, and untreated IRS2-knockout mice. However, NaW-treated IRS2-knockout mice showed tubular alterations resembling clear cells in the cortex, but not in the outer medulla, that were correlated with glycogen accumulation. Immunohistochemical detection of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, mostly expressed by renal proximal tubules, showed that altered tubules were of proximal origin. Our preliminary study suggests that IRS2 differentially regulates glycogen accumulation in renal tubules and that NaW treatment in the context of IRS2 ablation induces abnormal glycogen accumulation in cortical proximal tubules.

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“…(e) Na 2 WO 4 induces DNA damage (Guilbert et al, ; Kelly et al, ) and cell cycle arrest (Bertinat, Silva, et al, ; Guilbert et al, ; Liu et al, ; Osterburg et al, ), precluding cell senescence and the secretion of senescence‐associated products that can fuel cell transformation by targeting the tumor microenvironment (Sturmlechner et al, ). (f) Na 2 WO 4 stimulates cytokine secretion, among these the angiogenic factor VEGF‐A (Bertinat, Silva, et al, 2015) and the proinflammatory factors IL‐6, IL‐8, and MCP‐1 (Bertinat et al, ), which are critical players in tumor development and progression, acting in an autocrine and paracrine fashion. The Janus kinase (JAK)–signal transducer and activator of transcription (STAT)‐3 and ERK1/2 pathways are the major cascades activated by IL‐6 and IL‐8, but are also activated by different growth factors and show cross talk with many other signaling pathways (McGuire & Fitzpatrick, ; Taniguchi & Karin, ).…”

Section: Na2wo4 and Renal Carcinogenesis: Hypothesismentioning

confidence: 99%

“…(e) Na 2 WO 4 induces DNA damage (Guilbert et al, 2011;Kelly et al, 2013) and cell cycle arrest (Bertinat, Silva, et al, 2015;Guilbert et al, 2011;Liu et al, 2012;Osterburg et al, 2010), precluding cell senescence and the secretion of senescence-associated products that can fuel cell transformation by targeting the tumor microenvironment (Sturmlechner et al, 2017). (f) Na 2 WO 4 stimulates cytokine secretion, among these the angiogenic factor VEGF-A (Bertinat, Silva, et al, 2015) and the proinflammatory factors IL-6, IL-8, and MCP-1 (Bertinat et al, 2017), which are critical players in tumor development and progression, acting in an autocrine and paracrine fashion.…”

Section: Na 2 Wo 4 and Renal Carcinogenesis: Hypothesismentioning

confidence: 99%

“…T A B L E 2 Detrimental cancer-related Na 2 WO 4 effects Reported evidence Effect Model Reference DNA damage ↑ BU-11 cell line (in vitro) Guilbert et al (2011) ↑ BMS2 cell line (in vitro) Guilbert et al (2011) ↑ Primary murine bone marrow-derived developing B lymphocytes (in vitro) Guilbert et al (2011) ↑ Bone marrow from C57BL/6J mice (in vivo) Guilbert et al (2011) ↑ B lymphocytes from C57BL/6J mice (in vivo) Kelly et al (2013) Apoptosis ↑ Human peripheral blood lymphocytes (in vitro) Osterburg et al (2010) ↑ BU-11 cell line (in vitro) Guilbert et al (2011) ↑ Primary murine bone marrow-derived developing B lymphocytes (in vitro) Guilbert et al (2011) Cell cycle arrest ↑ Human peripheral blood lymphocytes (in vitro) Osterburg et al (2010) ↑ BU-11 cell line (in vitro) Guilbert et al (2011) ↑ BMS2 cell line (in vitro) Guilbert et al (2011) ↑ Primary murine bone marrow-derived developing B lymphocytes (in vitro) Guilbert et al (2011) ↑ PC-3 cell line (in vitro) Liu et al (2012) ↑ HK-2 cell line (in vitro) Bertinat, Silva, et al (2015) Histone methylation ↑ A549 cell line (in vitro) Laulicht-Glick et al (2017) ↑ BEAS-2B cell line (in vitro) Laulicht-Glick et al (2017) ↑ Liver from A/J mice (in vivo) Laulicht-Glick et al (2017) B-lymphocyte development ↓ B lymphocytes from C57BL/6J mice (in vivo) Kelly et al (2013) Immune response ↓ C57BL/6J mice (in vivo) Osterburg et al (2014) ↓ B 6 C 3 F 1 /N mice (in vivo) Frawley et al (2016) Carcinogenesis ↑ BEAS-2B cells injected in nude mice a Laulicht et al (2015) Breast cancer metastasis ↑ BALB/c mice (in vivo) Bolt et al (2015) Renal histopathological alterations ↑ Sprague-Dawley rats (in vivo) McCain et al (2015) Renal glycogen accumulation ↑ irs2 −/− diabetic mice (in vivo) Bertinat et al (2018) VEGF-A secretion ↑ HK-2 cell line (in vitro) Bertinat, Silva, et al (2015)IL-6, IL-8, MCP-1 secretion ↑ Primary cultures of human RPTEC (in vitro)Bertinat et al (2017) …”

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confidence: 99%

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Sodium tungstate: Is it a safe option for a chronic disease setting, such as diabetes?

Bertinat

Westermeier

Gatica

et al. 2018

Journal Cellular Physiology

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Diabetes is a complex metabolic disorder triggered by the deficient secretion of insulin by pancreatic β cells, the resistance of peripheral tissues to the action of the hormone, or both, and is characterized by chronic hyperglycemia leading to organ damage and failure. Tight glycemic control represents the best therapy to delay or stop progression of diabetes, with many antidiabetic drugs being commercially available nowadays. However, no ideal normoglycemic agent has been developed as yet, and those already available still induce hypoglycemia and/or weight gain as major side effects, worsening glycemic control. In this respect, the inorganic salt sodium tungstate (Na WO ) has been proven to offer a good antidiabetic alternative in different animal models of diabetes, reducing body weight and normalizing glycemia without causing hypoglycemic episodes. The mechanisms of action mediating the potent antidiabetic actions but also the spectrum of undesirable effects of Na WO are still poorly understood. In fact, along with its beneficial effects, Na WO has been consistently reported to be toxic and even carcinogenic. Given that Na WO is accumulated in the kidneys for elimination, here, we discuss a possible association between long-term Na WO treatment and a higher risk of renal carcinogenesis in diabetic individuals.

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Anti‐Diabetic Agent Sodium Tungstate Induces the Secretion of Pro‐ and Anti‐Inflammatory Cytokines by Human Kidney Cells

Cited by 11 publications

References 35 publications

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

The Antidiabetic Agent Sodium Tungstate Induces Abnormal Glycogen Accumulation in Renal Proximal Tubules from Diabetic IRS2-Knockout Mice

Sodium tungstate: Is it a safe option for a chronic disease setting, such as diabetes?

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