scholarly journals Sitagliptin ameliorates ER stress in diabetic kidney disease through upregulation of SIRT1

2021 ◽  
Vol 1 (1) ◽  
pp. 33-41
Author(s):  
Qunzi Zhang ◽  
Junjie Jia ◽  
Li He ◽  
Ying Fan ◽  
Niansong Wang
Keyword(s):  
Kidney Disease ◽  
Er Stress ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Er Homeostasis

Abstract Objectives Endoplasmic reticulum (ER) stress plays a significant role in the progression of diabetic kidney disease (DKD), and dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemic agents, exerting renal beneficial effects in DKD. Here, we investigated the role of DPP4 inhibitor Sitagliptin (Sita) in ER homeostasis in the kidneys of diabetic DBA2/J (D2) mice and in albumin-stimulated HK-2 cells. Methods and Results ER stress was observed both in vivo and in vitro, as reflected by notably increased glucose-regulated protein of 78 kDa (GRP78), CHOP, high phosphorylation of PERK (p-PERK), and cleaved caspase3 (c-CASP3), whereas Sita effectively attenuated these disorders. Meanwhile, Sita increased the expression of SIRT1 both in vivo and in vitro. To further validate the potential effects of SIRT1 in regulating ER stress, we regulated SIRT1 by siRNA and overexpressed plasmids in albumin-overloaded HK-2 cells. Elevated SIRT1 alleviated albumin-induced ER stress, while decreased SIRT1 further aggravated ER stress in albumin-treated HK-2 cells. Conclusion The results suggest that a novel mechanism links the DPP4 enzyme to ER stress during tubular injury in DKD and highlight that SIRT1 may be a potential target for managing DKD.

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.

scholarly journals Role of TGF-alpha in the progression of diabetic kidney disease

2017 ◽  
Vol 312 (6) ◽  
pp. F951-F962 ◽  
Author(s):  
Josef G. Heuer ◽  
Shannon M. Harlan ◽  
Derek D. Yang ◽  
Dianna L. Jaqua ◽  
Jeffrey S. Boyles ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Neutralizing Antibodies ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Renin Angiotensin System ◽  
Neutralizing Antibody ◽  
Diabetic Kidney

Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenal TGFA mRNA expression, as well as urine and serum TGFA, are increased in human DKD. We used a TGFA neutralizing antibody to determine the role of TGFA in two models of renal disease, the remnant surgical reduction model and the uninephrectomized (uniNx) db/db DKD model. In addition, the contribution of TGFA to DKD progression was examined using an adeno-associated virus approach to increase circulating TGFA in experimental DKD. In vivo blockade of TGFA attenuated kidney disease progression in both nondiabetic 129S6 nephron reduction and Type 2 diabetic uniNx db/db models, whereas overexpression of TGFA in uniNx db/db model accelerated renal disease. Therapeutic activity of the TGFA antibody was enhanced with renin angiotensin system inhibition with further improvement in renal parameters. These findings suggest a pathologic contribution of TGFA in DKD and support the possibility that therapeutic administration of neutralizing antibodies could provide a novel treatment for the disease.

scholarly journals The Role of DPP4 Activity in Cardiovascular Districts: In Vivo and In Vitro Evidence

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
L. Pala ◽  
C. M. Rotella
Keyword(s):  
Minimal Risk ◽  
Incretin Hormone ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Glucagon Like Peptide 1 ◽  
A Site

The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, since these drugs not only improve glycemia with minimal risk of hypoglycemia, but also have other extraglycemic beneficial effects. These agents, which are effective in improving glucose control, could also have positive effects on the incidence of cardiovascular events. The aim of this review is to summarize the present literature about the role of dipeptidyl peptidase 4 (DPP4) in cardiovascular districts, not only strictly correlated to its effect on glucagon-like peptide-1 (GLP-1) circulating levels, but also to what is known about possible cardiovascular actions. Actually, DPP4 is known to be present in many cells and tissues and its effects go beyond purely metabolic aspects. Almost always the inhibition of DPP4 activity is associated with improved cardiovascular profile, but it has shown to possess antithrombotic properties and these different effects could be connected with a site and/or species specificity of DPP4. Certainly, DPP4 seems to exert many functions, both directly and indirectly, on cardiovascular districts, opening new possibilities of prevention and treatment of complications at this level, not only in patients affected by diabetes mellitus.

scholarly journals S-Nitrosylation of RhoGAP Myosin9A Is Altered in Advanced Diabetic Kidney Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Qi Li ◽  
Delma Veron ◽  
Alda Tufro
Keyword(s):  
Kidney Disease ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Diabetic Mice ◽  
Post Translational Modification ◽  
No Donor ◽  
Diabetic Kidney ◽  
Rhoa Activity

The molecular pathogenesis of diabetic kidney disease progression is complex and remains unresolved. Rho-GAP MYO9A was recently identified as a novel podocyte protein and a candidate gene for monogenic FSGS. Myo9A involvement in diabetic kidney disease has been suggested. Here, we examined the effect of diabetic milieu on Myo9A expression in vivo and in vitro. We determined that Myo9A undergoes S-nitrosylation, a post-translational modification dependent on nitric oxide (NO) availability. Diabetic mice with nodular glomerulosclerosis and severe proteinuria associated with doxycycline-induced, podocyte-specific VEGF164 gain-of-function showed markedly decreased glomerular Myo9A expression and S-nitrosylation, as compared to uninduced diabetic mice. Immortalized mouse podocytes exposed to high glucose revealed decreased Myo9A expression, assessed by qPCR, immunoblot and immunocytochemistry, and reduced Myo9A S-nitrosylation (SNO-Myo9A), assessed by proximity link assay and biotin switch test, functionally resulting in abnormal podocyte migration. These defects were abrogated by exposure to a NO donor and were not due to hyperosmolarity. Our data demonstrate that high-glucose induced decrease of both Myo9A expression and SNO-Myo9A is regulated by NO availability. We detected S-nitrosylation of Myo9A interacting proteins RhoA and actin, which was also altered by high glucose and NO dependent. RhoA activity inversely related to SNO-RhoA. Collectively, data suggest that dysregulation of SNO-Myo9A, SNO-RhoA and SNO-actin may contribute to the pathogenesis of advanced diabetic kidney disease and may be amenable to therapeutic targeting.

scholarly journals Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Martin Haluzík ◽  
Jan Frolík ◽  
Ivan Rychlík
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Cardiovascular Complications ◽  
Special Focus ◽  
Renal Effects ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Increased Risk ◽  
Glucagon Like Peptide 1

Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4) inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1) dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

scholarly journals KCa3.1 Mediates Dysregulation of Mitochondrial Quality Control in Diabetic Kidney Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Chunling Huang ◽  
Hao Yi ◽  
Ying Shi ◽  
Qinghua Cao ◽  
Yin Shi ◽  
...  
Keyword(s):  
Quality Control ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Mice ◽  
Mitochondrial Quality Control ◽  
Diabetic Kidney ◽  
Hk2 Cells ◽  
Tgf Β1

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease. Mitochondrial quality control is primarily mediated by mitochondrial turnover and repair through mitochondrial fission/fusion and mitophagy. We have previously shown that blockade of the calcium-activated potassium channel KCa3.1 ameliorates diabetic renal fibrosis. However, the mechanistic link between KCa3.1 and mitochondrial quality control in diabetic kidney disease is not yet known. Transforming growth factor β1 (TGF-β1) plays a central role in diabetic kidney disease. Recent studies indicate an emerging role of TGF-β1 in the regulation of mitochondrial function. However, the molecular mechanism mediating mitochondrial quality control in response to TGF-β1 remains limited. In this study, mitochondrial function was assessed in TGF-β1-exposed renal proximal tubular epithelial cells (HK2 cells) transfected with scrambled siRNA or KCa3.1 siRNA. In vivo, diabetes was induced in KCa3.1+/+ and KCa3.1−/− mice by low-dose streptozotocin (STZ) injection. Mitochondrial fission/fusion-related proteins and mitophagy markers, as well as BCL2 interacting protein 3 (BNIP3) (a mitophagy regulator) were examined in HK2 cells and diabetic mice kidneys. The in vitro results showed that TGF-β1 significantly inhibited mitochondrial ATP production rate and increased mitochondrial ROS (mtROS) production when compared to control, which was normalized by KCa3.1 gene silencing. Increased fission and suppressed fusion were found in both TGF-β1-treated HK2 cells and diabetic mice, which were reversed by KCa3.1 deficiency. Furthermore, our results showed that mitophagy was inhibited in both in vitro and in vivo models of diabetic kidney disease. KCa3.1 deficiency restored abnormal mitophagy by inhibiting BNIP3 expression in TGF-β1-induced HK2 cells as well as in the diabetic mice. Collectively, these results indicate that KCa3.1 mediates the dysregulation of mitochondrial quality control in diabetic kidney disease.

scholarly journals Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease

2021 ◽  
Vol 22 (6) ◽  
pp. 2839
Author(s):  
Asfia Soomro ◽  
Jackie Trink ◽  
Kian O’Neil ◽  
Renzhong Li ◽  
Safaa Naiel ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cell Surface ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Diabetic Kidney ◽  
Rhoa Activation ◽  
Cell Surface Grp78

Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD.

FC 087MIR-155/SOCS1 REGULATORY LOOP INFLUENCES DIABETIC KIDNEY DISEASE BY JAK/STAT PATHWAY MODULATION

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Ignacio Prieto ◽  
Luna Jimenez-Castilla ◽  
Iolanda Lazaro ◽  
Susana Bernal-Uribe ◽  
Laura Lopez-Sanz ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Regulatory Loop ◽  
And Oxidative Stress ◽  
Stat Pathway

Abstract Background and Aims Diabetic nephropathy is the leading cause of chronic kidney disease worldwide. Hyperglycemia in concert with cytokines activate Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway and induce gene expression of many inflammatory and oxidative stress mediators, which are critical events at all stages of diabetic kidney disease. Suppressor of cytokine signaling 1 (SOCS1) is a STAT-inducible protein and a negative feedback regulator of JAK/STAT pathway. The microRNA-155 is an epigenetic modulator of SOCS1 gene by repressing its translation and, at the same time, is a transcriptional target of STAT, thus completing another regulatory loop of JAK/STAT pathway. Therefore, our aim was to explore the interplay between miR-155 and JAK/STAT/SOCS1 axis in experimental diabetic nephropathy. Method In streptozotocin-induced type 1 diabetic aged mice (wild-type and apolipoprotein E (apoE) knockout) we analyzed the kidney levels of miR-155 and markers of renal damage, inflammation and oxidative stress. In vitro, the expression of miR-155, SOCS1 and STAT1 in mesangial, tubuloepithelial and macrophage cell lines were modulated by silencing/inhibition or overexpression/mimicking experiments to further determine the JAK/STAT pathway activation and expression of downstream target genes. Results In vivo, type 1 diabetes significantly upregulated miR-155 expression in kidneys from both wild-type and apoE knockout mice (1.8- and 4.5-fold vs respective non-diabetic controls). The miR-155 levels directly correlated with parameters of renal damage (serum creatinine, albuminuria, kidney-to-body weight ratio and renal score) and the mRNA expression of chemokines (Ccl2 and Ccl5) and pro-oxidant enzymes (Nox2 and Nox4), but inversely with antioxidant genes (Sod1 and Cat). In vitro, the expression of miR-155 was increased in renal cells and macrophages exposed to hyperglycemia and/or inflammatory conditions. Overexpression of miR-155 reduced SOCS1 expression, enhanced STAT1 and STAT3 activation and pro-inflammatory cytokines and chemokines (Il6, Tnfa, Ccl2 and Cxcl10) expression. By contrast, miR-155 antagonist upregulated SOCS1 and had a protective effect on renal cells by decreasing STAT1/3 phosphorylation and pro-inflammatory gene expression. Additionally, loss- or gain-of function experiments indicate a direct implication of SOCS1 in the regulation of miR-155 expression by STAT transcription factors. Conclusion Our study indicates a pro-inflammatory role of miR-155 in diabetic kidney disease by downregulating renal expression of SOCS1. Therefore, antagonism of miR-155 may have a renoprotective effect in diabetic nephropathy through SOCS1-mediated feedback inhibition of JAK/STAT overactivation. Ongoing in vivo studies with miR-155 inhibitor in experimental diabetes will clarify its role in the development and progression of diabetic nephropathy.

scholarly journals Activated Alpha 2-Macroglobulin Is a Novel Mediator of Mesangial Cell Profibrotic Signaling in Diabetic Kidney Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1112
Author(s):  
Jackie Trink ◽  
Renzhong Li ◽  
Yaseelan Palarasah ◽  
Stéphan Troyanov ◽  
Thomas E. Andersen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Diabetic Patients ◽  
Glomerular Mesangial Cells ◽  
Inhibitory Peptide ◽  
Diabetic Kidney ◽  
Akt Activation

Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients’ serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic Akita and CD1 mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFβ1). In patients with established DKD, urinary α2M* and TGFβ1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.

Sign in / Sign up

Export Citation Format

Share Document