Podocytes, Signaling Pathways, and Vascular Factors in Diabetic Kidney Disease

Brosius, Frank C.; Coward, Richard J M

doi:10.1053/j.ackd.2014.03.011

Cited by 57 publications

(51 citation statements)

References 78 publications

(89 reference statements)

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“…The general accuracy of this approach, however, is still reasonable based on previously reported associations [13]. Indeed, our data using this relatively unbiased approach confirm the involvement of pathways that have been identified to be important in both DPN and DN [25, 38, 39]. …”

Section: Discussionsupporting

confidence: 84%

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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Section: Discussionsupporting

confidence: 84%

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

et al. 2016

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“…In this context, the routine metabolic signaling that regulates insulin-dependent glucose transport/utilization can occur in opposition to growth signaling pathways that are also dependent on insulin. These pathways include serine kinases that are redox-sensitive, including extracellular receptor kinase, Rho kinase, JUN NH 2 -terminal kinase, and the mammalian target of rapamycin/serine kinase 1 signaling pathways [11,12,13,14,15,16,17] that regulate growth, hypertrophy, and fibrotic pathways. These pathways are also under the control of other neurohumoral pathways in insulin-resistant states, i.e., the sympathetic nervous system and the renin-angiotensin-aldosterone system [10,18,19].…”

Section: Mechanisms Of Insulin Resistance and Impact Of Insulin On Thmentioning

confidence: 99%

Insulin Resistance in Kidney Disease: Is There a Distinct Role Separate from That of Diabetes or Obesity

Whaley‐Connell¹,

Sowers

2017

Cardiorenal Med

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Insulin resistance is a central component of the metabolic dysregulation observed in obesity, which puts one at risk for the development of type 2 diabetes and complications related to diabetes such as chronic kidney disease. Insulin resistance and compensatory hyperinsulinemia place one at risk for other risk factors such as dyslipidemia, hypertension, and proteinuria, e.g., development of kidney disease. Our traditional view of insulin actions focuses on insulin-sensitive tissues such as skeletal muscle, liver, adipose tissue, and the pancreas. However, insulin also has distinct actions in kidney tissue that regulate growth, hypertrophy, as well as microcirculatory and fibrotic pathways which, in turn, impact glomerular filtration, including that governed by tubuloglomerular feedback. However, it is often difficult to discern the distinct effects of excess circulating insulin and impaired insulin actions, as exist in the insulin resistance individual, from the associated effects of obesity or elevated systolic blood pressure on the development and progression of kidney disease over time. Therefore, we review the experimental and clinical evidence for the distinct impact of insulin resistance on kidney function and disease.

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“…The serine/threonine kinase mTOR forms two distinct functional complexes, mTORC1 and mTORC2 [16]. The mTORC1 complex including at least three additional components, Raptor, mLST8, and FKBP12, is rapamycin-sensitive since the interaction of the rapamycin and FKBP12 interferes with the binding of Raptor to mTOR [17].…”

Section: Introductionmentioning

confidence: 99%

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

Zhang

Wang

Ren

et al. 2016

Cell Physiol Biochem

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Background/Aims: Although increased expression and gain function of transient receptor potential cation channel 6 (TRPC6) has been associated with the pathogenesis of some proteinuric glomerular diseases, it remains elusive how TRPC6 participates in the process of podocyte damage. Methods: The potential signaling responsible for TRPC6 activation was investigated using immunoblot assays in an in vitro podocyte injury model induced by Adriamycin (ADR). Podocyte apoptosis was measured using FITC-conjugated Annexin V and Propidium Iodide staining. The channel activity of TRPC6 was assessed using the Ca²⁺ influx assay. Results: Increase of TRPC6 expression was detected in ADR-treated podocytes, and TRPC6 knockdown significantly decreased ADR-induced podocytes apoptosis. Following ADR treatment, phospho-mTOR^Ser2481 and phospho-Akt^Ser473 was significantly increased in a time-dependent manner, whereas phospho-mTOR^Ser2448 and phospho-p70S6K^Thr389 showed no change. ADR-induced apoptosis was prevented by ku0063794 (a dual mTOR complexes inhibitor), not by rapamycin (a specific mTORC1 inhibitor). Furthermore, nuclear translocation of NFκB/p65 was detected in ADR-treated podocytes, which was prevented by an Akt inhibitor triciribine. Of note, NFκB inhibitor PDTC prevented ADR-induced increase of TRPC6, and decreased ADR-induced apoptosis. We found that Akt activation and NFκB nuclear translocation was significantly inhibited by knockdown of mTORC2 protein Rictor, not by mTORC1 protein Raptor. In comparison with control, the Ca²⁺ influx was significantly increased in ADR-treated podocytes, which was remarkably prevented by TRPC6 knockdown. ADR-induced increase of TRPC6 channel activity was dramatically prevented by ku0063794, but not by rapamycin. Additionally, knockdown of Rictor, not Raptor, prevented ADR-induced increase of the Ca²⁺ influx. Moreover, the application of NFκB inhibitor PDTC also prevented the Ca²⁺ influx in ADR-treated podocytes. Conclusions: Our findings revealed that the mTORC2/Akt/NFκB pathway-mediated activation of TRPC6 participates in ADR-induced podocyte apoptosis.

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Podocytes, Signaling Pathways, and Vascular Factors in Diabetic Kidney Disease

Cited by 57 publications

References 78 publications

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

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

Insulin Resistance in Kidney Disease: Is There a Distinct Role Separate from That of Diabetes or Obesity

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

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