scholarly journals Connectivity mapping identifies BI-2536 as a potential drug to treat diabetic kidney disease

2020 ◽  
Author(s):  
Ada Admin ◽  
Lu Zhang ◽  
Zichen Wang ◽  
Ruijie Liu ◽  
Zhengzhe Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Transcriptional Activation ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Novel Therapy ◽  
Integrated Network ◽  
Diabetic Kidney ◽  
Connectivity Mapping ◽  
Bi 2536

Diabetic kidney disease (DKD) remains the most common cause of kidney failure and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in-vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor were of members of the TNF-α/NF-kB, JAK/STAT, and TGF-β/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-kB and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.

scholarly journals Connectivity mapping identifies BI-2536 as a potential drug to treat diabetic kidney disease

2020 ◽  
Author(s):  
Ada Admin ◽  
Lu Zhang ◽  
Zichen Wang ◽  
Ruijie Liu ◽  
Zhengzhe Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Transcriptional Activation ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Novel Therapy ◽  
Integrated Network ◽  
Diabetic Kidney ◽  
Connectivity Mapping ◽  
Bi 2536

Diabetic kidney disease (DKD) remains the most common cause of kidney failure and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in-vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor were of members of the TNF-α/NF-kB, JAK/STAT, and TGF-β/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-kB and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.

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.

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.

scholarly journals Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease

Diabetes ◽  
2020 ◽  
pp. db200580
Author(s):  
Lu Zhang ◽  
Zichen Wang ◽  
Ruijie Liu ◽  
Zhengzhe Li ◽  
Jennifer Lin ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Potential Drug ◽  
Diabetic Kidney ◽  
Connectivity Mapping ◽  
Bi 2536

scholarly journals miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mitsuo Kato ◽  
Maryam Abdollahi ◽  
Ragadeepthi Tunduguru ◽  
Walter Tsark ◽  
Zhuo Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Mitochondrial Fission ◽  
Major Complication ◽  
Body Weight Loss ◽  
Diabetic Kidney ◽  
Guide Rna ◽  
And Oxidative Stress

AbstractDiabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5′-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for 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 BKCa Mediates Dysfunction in High Glucose Induced Mesangial Cell Injury via TGF-β1/Smad2/3 Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Zhigui Wu ◽  
Wenxian Yin ◽  
Mengqi Sun ◽  
Yuankai Si ◽  
Xiaoxiao Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Diabetic Kidney

Objective. To explore the role and mechanism of BKCa in diabetic kidney disease. Methods. Rat mesangial cells (MCs) HBZY-1 were cultured with high glucose to simulate the high-glucose environment of diabetic kidney disease in vivo. The effects of large conductance calcium-activated potassium channel (BKCa) on proliferation, migration, and apoptosis of HBZY-1 cells were observed. The contents of transforming growth factor beta 1 (TGF-β1), Smad2/3, collagen IV (Col IV), and fibronectin (FN) in the extracellular matrix were also observed. Results. High glucose significantly damaged HBZY-1 cells, which enhanced the ability of cell proliferation, migration, and apoptosis, and increased the secretion of Col IV and FN. Inhibition of BKCa and TGF-β1/Smad2/3 signaling pathways can inhibit the proliferation, migration, and apoptosis of HBZY-1 cells and suppress the secretion of Col IV and FN. The effect of excitation is the opposite. Conclusions. BKCa regulates mesangial cell proliferation, migration, apoptosis, and secretion of Col IV and FN and is associated with TGF-β1/Smad2/3 signaling pathway.

scholarly journals Suppressed ER‐associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease

2020 ◽  
Vol 34 (11) ◽  
pp. 15577-15590
Author(s):  
Daisuke Fujimoto ◽  
Takashige Kuwabara ◽  
Yusuke Hata ◽  
Shuro Umemoto ◽  
Tomoko Kanki ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cross Talk ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Podocyte Injury ◽  
Diabetic Kidney

scholarly journals Glomerular endothelial cell injury and cross talk in diabetic kidney disease

2015 ◽  
Vol 308 (4) ◽  
pp. F287-F297 ◽  
Author(s):  
Jia Fu ◽  
Kyung Lee ◽  
Peter Y. Chuang ◽  
Zhihong Liu ◽  
John Cijiang He
Keyword(s):  
Endothelial Cell ◽  
Kidney Disease ◽  
Cross Talk ◽  
Diabetic Kidney Disease ◽  
Cell Injury ◽  
Mesangial Cells ◽  
Glomerular Endothelial Cell ◽  
Glomerular Cell ◽  
Diabetic Kidney ◽  
Endothelial Cell Surface

Diabetic kidney disease (DKD) remains a leading cause of new-onset end-stage renal disease (ESRD), and yet, at present, the treatment is still very limited. A better understanding of the pathogenesis of DKD is therefore necessary to develop more effective therapies. Increasing evidence suggests that glomerular endothelial cell (GEC) injury plays a major role in the development and progression of DKD. Alteration of the glomerular endothelial cell surface layer, including its major component, glycocalyx, is a leading cause of microalbuminuria observed in early DKD. Many studies suggest a presence of cross talk between glomerular cells, such as between GEC and mesangial cells or GEC and podocytes. PDGFB/PDGFRβ is a major mediator for GEC and mesangial cell cross talk, while vascular endothelial growth factor (VEGF), angiopoietins, and endothelin-1 are the major mediators for GEC and podocyte communication. In DKD, GEC injury may lead to podocyte damage, while podocyte loss further exacerbates GEC injury, forming a vicious cycle. Therefore, GEC injury may predispose to albuminuria in diabetes either directly or indirectly by communication with neighboring podocytes and mesangial cells via secreted mediators. Identification of novel mediators of glomerular cell cross talk, such as microRNAs, will lead to a better understanding of the pathogenesis of DKD. Targeting these mediators may be a novel approach to develop more effective therapy for DKD.

scholarly journals Diabetic Kidney Disease Alters the Transcriptome and Function of Human Adipose-Derived Mesenchymal Stromal Cells but Maintains Immunomodulatory and Paracrine Activities Important for Renal Repair

2021 ◽  
Author(s):  
LaTonya J. Hickson ◽  
Alfonso Eirin ◽  
Sabena M. Conley ◽  
Timucin Taner ◽  
Xiaohui Bian ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Stromal Cells ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Inflammatory Marker ◽  
Patient Characteristics ◽  
Rna Seq ◽  
Diabetic Kidney

<a>Mesenchymal stem/stromal cells (MSC) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 DKD participants and 16 controls were assessed for cell surface markers, tri-lineage differentiation, RNA-sequencing (RNA-seq), <i>in vitro</i> function (co-culture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD- <i>vs</i>. Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved but migration was reduced. DKD-MSC with and without interferon-γ priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC-medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase-1 and prostaglandin-E2) and pro-repair factors (hepatocyte growth factor and stromal cell-derived factor-1) but lower Interleukin-6 vs. Control-MSC-medium. DKD-MSC-medium protected high glucose plus transforming growth factor-β-exposed HK-2 cells by reducing apoptotic, fibrotic and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics including age, gender, body mass index, hemoglobin A1c, kidney function or urine albumin excretion. However, senescence-associated-β-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while </a><a>DKD altered the transcriptome and migratory function of culture-expanded MSC, DKD-MSC functionality, trophic factor secretion and immunomodulatory activities contributing to repair remained intact. </a>These observations support testing patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.

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