Role of Endothelial Glucocorticoid Receptor in the Pathogenesis of Kidney Diseases

Przybyciński, Jarosław; Drożdżal, Sylwester; Domański, Leszek; Dziedziejko, Violetta; Pawlik, Andrzej

doi:10.3390/ijms222413295

Cited by 5 publications

(3 citation statements)

References 114 publications

(135 reference statements)

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“…Glucocorticoids are steroid hormones that are often used for inflammation and immune suppression across multiple diseases by repressing the activity of immunologic transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), AP-1, and T-bet (Hudson et al 2018 ). Additionally, glucocorticoids have more recently been investigated for potential pathway involvement in nephrological diseases and in pathways such as Wnt signaling and autophagy (Przybyciński et al 2021 ). While neurology/psychology-indicated drugs do have the most compounds annotated in the Drug Repurposing Hub we used for annotation, further investigation is warranted, especially due to the noted comorbidity between ADPKD and depression (Simms et al 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Wilk

Howton

Fisher

et al. 2023

Mol Med

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Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. Methods As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates’ target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. Results With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo. Conclusion Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Wilk

Howton

Fisher

et al. 2023

Mol Med

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“…Previous research and our findings suggest that abnormal light exposure may influence CORT secretion. Glucocorticoids have multiple functions and have been widely used to treat various diseases, including kidney disease [34]. They affect immune cells and induce severe renal injury [35].…”

Section: Discussionmentioning

confidence: 99%

Continuous Monochromatic Blue Light Exacerbates High-Fat Diet-Induced Kidney Injury via Corticosterone-Mediated Oxidative Stress

et al. 2023

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Excessive illumination is one of the most severe environmental factors that impacts the organism. There is growing evidence that obesity significantly contributes to the onset of chronic kidney disease. However, the effect of continuous light on the kidney and which color can produce an apparent phenomenon remains elusive. In this study, C57BL/6 mice given either a normal diet (LD-WN) or a high-fat diet (LD-WF) were subjected to a light cycle of 12 h of illumination followed by 12 h of darkness for 12 weeks. Meanwhile, 48 high-fat diet mice were given a 24 h monochromatic light exposure of varying colors (white, LL-WF; blue, LL-BF; green, LL-GF) for 12 weeks. As expected, the LD-WF mice showed significant obesity, kidney injury, and renal dysfunction compared with the LD-WN group. LL-BF mice had worse kidney injury than LD-WF mice, including higher Kim-1 and Lcn2. The kidney of the LL-BF group showed marked glomerular and tubular injury, with decreased levels of Nephrin, Podocin, Cd2ap, and α-Actinin-4 compared to LD-WF. LL-BF also reduced the antioxidant capacity, including GSH-Px, CAT, and T-AOC, increased the production of MDA, and inhibited the activation of the NRF2/HO-1 signaling pathway. Furthermore, LL-BF upregulated the mRNA levels of the pro-inflammatory factors Tnf-α, Il-6, and Mcp-1, decreasing the inhibitory inflammatory Il-4 expression. We observed increased plasma corticosterone (CORT), renal glucocorticoid receptors (GR) expression, Hsp90, Hsp70, and P23 mRNA levels. These findings suggested that LL-BF increased CORT secretion and affected glucocorticoid receptors (GR) in comparison to the LD-WF group. Moreover, in vitro research demonstrated that CORT treatment increased oxidative stress and inflammation, which was counteracted by adding a GR inhibitor. Thus, the sustained blue light worsened kidney damage, possibly by inducing elevated CORT and increasing oxidative stress and inflammation via GR.

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“…(75) Additionally, glucocorticoids have more recently been investigated for potential pathway involvement in nephrological diseases and in pathways such as Wnt signaling and autophagy. (76) While neurology/psychology-indicated drugs do have the most compounds annotated in the Drug Repurposing Hub we used for annotation further investigation is warranted, especially due to the noted comorbidity between ADPKD and depression. (77)…”

Section: Discussionmentioning

confidence: 99%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mousePkd2model gene expression reversion

Wilk

Howton

Fisher

et al. 2022

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) isone of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates' target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. With this approach, we prioritized 29 unique drug targets differentially expressed in ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine. Collectively, these indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.

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Role of Endothelial Glucocorticoid Receptor in the Pathogenesis of Kidney Diseases

Cited by 5 publications

References 114 publications

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Continuous Monochromatic Blue Light Exacerbates High-Fat Diet-Induced Kidney Injury via Corticosterone-Mediated Oxidative Stress

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mousePkd2model gene expression reversion

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