JAK inhibition and progressive kidney disease

Brosius, Frank C.; He, John Cijiang

doi:10.1097/mnh.0000000000000079

Cited by 85 publications

(54 citation statements)

References 78 publications

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“…31,32 Jak1 is a membrane protein whose kinase activity targets STAT proteins that are subsequently translocated to the nucleus to target specific gene transcription. Although most intensively studied for their important roles in cytokine signaling, modulating the immune response and oncogenesis, mutations in the proteins present in this pathway, including Jak1, cause a number of different diseases, 33,34 and are responsible for numerous hepatocellular adenomas. 35 Additionally, the pathway is evolutionarily conserved and functions in transducing extracellular stimuli to the transcriptional apparatus.…”

Section: Resultsmentioning

confidence: 99%

An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels

McLendon

Davis

Gulick

et al. 2017

Circulation Research

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Rationale Post-mitotic cells such as cardiomyocytes appear to be particularly susceptible to proteotoxic stimuli, and large, proteinaceous deposits are characteristic of the Desmin Related Cardiomyopathies and crystallin cardiomyopathic diseases. Increased activity of protein clearance pathways in the cardiomyocyte such as proteasomal degradation and autophagy have proven to be beneficial in maintaining cellular and cardiac function in the face of multiple proteotoxic insults, holding open the possibility of targeting these processes for the development of effective therapeutics. Objective Here we undertake an unbiased, total genome screen for RNA transcripts and their protein products that impact on aggregate accumulations in the cardiomyocytes. Methods and Results Primary mouse cardiomyocytes that accumulate aggregates as a result of a mutant αB crystallin causative for human Desmin Related Cardiomyopathy were used for a total genome-wide screen to identify gene products that impacted on aggregate formation. We infected cardiomyocytes using a short hairpin RNA lentivirus library in which the mouse genome was represented. The screen identified multiple candidates in a number of cell signaling pathways that were able to mediate significant decreases in aggregate levels. Conclusions Subsequent validation of one of these candidates, Janus kinase 1 (Jak1), a tyrosine kinase of the non-receptor type, confirmed the usefulness of this approach in identifying previously unsuspected players in proteotoxic processes.

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Section: Resultsmentioning

confidence: 99%

An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels

McLendon

Davis

Gulick

et al. 2017

Circulation Research

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“…It was found that SOCS3 proteins suppress the JAK/STAT signaling that triggers their expression . It seems that the strongest expression of SOCS proteins occurs in proximal tubule epithelia and glomerular cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of liraglutide on the Janus kinase/signal transducer and transcription activator (JAK/STAT) pathway in diabetic kidney disease in db/db mice and in cultured endothelial cells

Zitman‐Gal

Einbinder

Ohana

et al. 2019

Journal of Diabetes

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Background Emerging evidence demonstrates the involvement of Janus tyrosine kinase/signal transducer and transcription activator (JAK/STAT) proteins in the pathophysiology of diabetic kidney disease (DKD). The JAK/STAT pathway is involved in the inflammatory response and endothelial cell dysfunction observed in DKD. The glucagon‐like peptide‐1 (GLP‐1) analog liraglutide is an effective treatment for type 2 diabetes because it improves the inflammatory changes observed in experimental models of DKD. This study used db/db mice and endothelial cells (ECs) to determine the effect of diabetic environment on the JAK/STAT pathway and to assess the potential effect of liraglutide (200 μg/kg) in both models. Methods Diabetic db/db mice (12 weeks old) were treated with liraglutide for 14 weeks. The kidneys were then perfused with saline and removed for mRNA, protein, and immunohistochemical analyses. Endothelial cells were stimulated advanced glycation end products (AGEs) (200 μg/μL) glucose (200 mg/dL) and liraglutide (100 nM) for 24 hours. Total RNA and protein were extracted and analyzed for expression of JAK/STAT signaling. Results Phosphorylated (p‐) STAT3 was significantly upregulated in db/db mice compared with non‐diabetic mice. Liraglutide significantly downregulated p‐STAT3 protein expression in db/db mice. In db/db mice, p‐STAT3 was primarily expressed in the glomeruli, whereas p‐JAK2 was also expressed in kidney tubules. In ECs, liraglutide treatment prevented increased expression of p‐STAT3 and p‐JAK2. Liraglutide inhibited the target gene suppressor of cytokine signaling 3 (SOCS3) and sirtuin 1 (SIRT1) in db/db mice and in cultured EC. Conclusions This study suggests that the GLP‐1 analog liraglutide inhibits the JAK/STAT pathway, which participates in intracellular processes in experimental models of diabetes.

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“…With JAK–STAT pathways being highly enriched in shared networks between patients and murine models of DN [13], and with rodent models of both type 1 and type 2 diabetes DN displaying improved kidney function following JAK–STAT inhibitor treatment [32, 33], this signalling pathway appears to be a viable therapeutic target. Indeed, clinical trials targeting the JAK–STAT pathway are currently underway for treatment of DN [34]. There is also evidence demonstrating a role for JAK–STAT signalling in DPN progression.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional networks of murine diabetic peripheral neuropathy and nephropathy: common and distinct gene expression patterns

et al. 2016

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Aims/hypothesis Diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN) are two common microvascular complications of type 1 and type 2 diabetes mellitus that are associated with a high degree of morbidity. In this study, using a variety of systems biology approaches, our aim was to identify common and distinct mechanisms underlying the pathogenesis of these two complications. Methods Our previously published transcriptomic datasets of peripheral nerve and kidney tissue, derived from murine models of type 1 diabetes (streptozotocin-injected mice) and type 2 diabetes (BKS-db/db mice) and their respective controls, were collected and processed using a unified analysis pipeline so that comparisons could be made. In addition to looking at genes and pathways dysregulated in individual datasets, pairwise comparisons across diabetes type and tissue type were performed at both gene and transcriptional network levels to complete our proposed objective. Results Gene-level analysis identified exceptionally high levels of concordant gene expression in DN (94% of 2,433 genes), but not in DPN (55% of 1,558 genes), between type 1 diabetes and type 2 diabetes. These results suggest that common pathogenic mechanisms exist in DN across diabetes type, while in DPN the mechanisms are more distinct. When these dysregulated genes were examined at the transcriptional network level, we found that the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway was significantly dysregulated in both complications, irrespective of diabetes type. Conclusions/interpretation Using a systems biology approach, our findings suggest that common pathogenic mechanisms exist in DN across diabetes type, while in DPN the mechanisms are more distinct. We also found that JAK–STAT signalling is commonly dysregulated among all datasets. Using such approaches, further investigation is warranted to determine whether the same changes are observed in patients with diabetic complications.

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JAK inhibition and progressive kidney disease

Cited by 85 publications

References 78 publications

An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels

An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels

Effect of liraglutide on the Janus kinase/signal transducer and transcription activator (JAK/STAT) pathway in diabetic kidney disease in db/db mice and in cultured endothelial cells

Transcriptional networks of murine diabetic peripheral neuropathy and nephropathy: common and distinct gene expression patterns

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