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Article ; Online: Retinoic acid receptor α activity in proximal tubules prevents kidney injury and fibrosis.

DiKun, Krysta M / Tang, Xiao-Han / Fu, Leiping / Choi, Mary E / Lu, Changyuan / Gudas, Lorraine J

Proceedings of the National Academy of Sciences of the United States of America

2024 Volume 121, Issue 7, Page(s) e2311803121

Abstract: Chronic kidney disease (CKD) is characterized by a gradual loss of kidney function and affects ~13.4% of the global population. Progressive tubulointerstitial fibrosis, driven in part by proximal tubule (PT) damage, is a hallmark of late stages of CKD ... ...

Abstract	Chronic kidney disease (CKD) is characterized by a gradual loss of kidney function and affects ~13.4% of the global population. Progressive tubulointerstitial fibrosis, driven in part by proximal tubule (PT) damage, is a hallmark of late stages of CKD and contributes to the development of kidney failure, for which there are limited treatment options. Normal kidney development requires signaling by vitamin A (retinol), which is metabolized to retinoic acid (RA), an endogenous agonist for the RA receptors (RARα, β, γ). RARα levels are decreased in a mouse model of diabetic nephropathy and restored with RA administration; additionally, RA treatment reduced fibrosis. We developed a mouse model in which a spatiotemporal (tamoxifen-inducible) deletion of RARα in kidney PT cells of adult mice causes mitochondrial dysfunction, massive PT injury, and apoptosis without the use of additional nephrotoxic substances. Long-term effects (3 to 4.5 mo) of RARα deletion include increased PT secretion of transforming growth factor β1, inflammation, interstitial fibrosis, and decreased kidney function, all of which are major features of human CKD. Therefore, RARα's actions in PTs are crucial for PT homeostasis, and loss of RARα causes injury and a key CKD phenotype.
MeSH term(s)	Animals ; Humans ; Mice ; Disease Models, Animal ; Fibrosis ; Kidney/metabolism ; Kidney Tubules, Proximal/metabolism ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/prevention & control ; Retinoic Acid Receptor alpha/genetics ; Retinoic Acid Receptor alpha/metabolism ; Tretinoin/pharmacology ; Tretinoin/metabolism
Chemical Substances	Retinoic Acid Receptor alpha ; Tretinoin (5688UTC01R) ; Rara protein, mouse
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2311803121
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Article ; Online: Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease.

Melis, Marta / Trasino, Steven E / Tang, Xiao-Han / Rappa, Andrew / Zhang, Tuo / Qin, Lihui / Gudas, Lorraine J

International journal of molecular sciences

2023 Volume 24, Issue 15

Abstract: In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the ... ...

Abstract	In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data indicate that a RARβ agonist limits the pathology of alcohol-related liver disease. Thus, we generated liver-specific AlbCre-RARβ knockout (BKO) mice and compared them to wild type (WT) mice in an early ALD model. Both strains showed similar blood ethanol concentrations and ETOH-metabolizing enzymes. However, the livers of pair-fed-BKO and ETOH-BKO mice developed higher levels of steatosis and triglycerides than pair-fed-WT and ETOH-WT mice. The increased hepatic steatosis observed in the pair-fed-BKO and ETOH-BKO mice was associated with higher lipid synthesis/trafficking transcripts and lower beta-oxidation transcripts. ETOH-BKO mice also exhibited a higher integrated stress response (ISR) signature, including higher transcript and protein levels of ATF4 and its target, 4-EBP1. In human hepatocytes (HepG2) that lack RARβ (RARβ-KO), ETOH treatments resulted in greater reactive oxygen species compared to their parental cells. Notably, even without ETOH, ATF4 and 4-EBP1 protein levels were higher in the RARβ-KO cells than in their parental cells. These 4-EBP1 increases were greatly attenuated in cultured ATF4-deficient and RARβ/ATF4-deficient HepG2, suggesting that RARβ is a crucial negative regulator of 4-EBP1 through ATF4 in cultured hepatocytes. Here, we identify RARβ as a negative regulator of lipid metabolism and cellular stress in ALD.
MeSH term(s)	Mice ; Humans ; Animals ; Ethanol/toxicity ; Ethanol/metabolism ; Vitamin A/metabolism ; Mice, Knockout ; Liver Diseases, Alcoholic/metabolism ; Fatty Liver/metabolism ; Hepatocytes/metabolism ; Liver/metabolism ; Receptors, Retinoic Acid/genetics ; Receptors, Retinoic Acid/metabolism
Chemical Substances	retinoic acid receptor beta ; Ethanol (3K9958V90M) ; Vitamin A (11103-57-4) ; Receptors, Retinoic Acid
Language	English
Publishing date	2023-07-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241512035
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Article ; Online: Novel genetically engineered mouse models for clear cell renal cell carcinoma.

van der Mijn, Johannes C / Laursen, Kristian B / Fu, Leiping / Khani, Francesca / Dow, Lukas E / Nowak, Dawid G / Chen, Qiuying / Gross, Steven S / Nanus, David M / Gudas, Lorraine J

Scientific reports

2023 Volume 13, Issue 1, Page(s) 8246

Abstract: Genetically engineered mouse models (GEMMs) are important immunocompetent models for research into the roles of individual genes in cancer and the development of novel therapies. Here we use inducible CRISPR-Cas9 systems to develop two GEMMs which aim to ...

Abstract	Genetically engineered mouse models (GEMMs) are important immunocompetent models for research into the roles of individual genes in cancer and the development of novel therapies. Here we use inducible CRISPR-Cas9 systems to develop two GEMMs which aim to model the extensive chromosome p3 deletion frequently observed in clear cell renal cell carcinoma (ccRCC). We cloned paired guide RNAs targeting early exons of Bap1, Pbrm1, and Setd2 in a construct containing a Cas9
MeSH term(s)	Male ; Humans ; Mice ; Animals ; Infant ; Carcinoma, Renal Cell/pathology ; Tumor Suppressor Proteins/genetics ; Kidney Neoplasms/pathology ; Mutation ; Promoter Regions, Genetic
Chemical Substances	Tumor Suppressor Proteins
Language	English
Publishing date	2023-05-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-35106-7
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Benjamin, Dalyia N / O'Donovan, Tracey R / Laursen, Kristian B / Orfali, Nina / Cahill, Mary R / Mongan, Nigel P / Gudas, Lorraine J / McKenna, Sharon L

Frontiers in oncology

2022 Volume 12, Page(s) 848517

Abstract: Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all- ...

Abstract	Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all-
Language	English
Publishing date	2022-02-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.848517
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Article: Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma.

Laursen, Kristian B / Chen, Qiuying / Khani, Francesca / Attarwala, Nabeel / Gross, Steve S / Dow, Lukas / Nanus, David M / Gudas, Lorraine J

Frontiers in oncology

2021 Volume 11, Page(s) 783856

Abstract: Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial ... ...

Abstract	Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation. Its role in ccRCC, however, remains enigmatic. We utilized our established ccRCC model, termed Transgenic Cancer of the Kidney (TRACK), to generate a novel genetically engineered mouse model in which dox-regulated expression of an shRNA decreases Ndufa4l2 levels specifically in the renal proximal tubules (PT). This targeted knockdown of Ndufa4l2 reduced the accumulation of neutral renal lipid and was associated with decreased levels of the ccRCC markers carbonic anhydrase 9 (CA9) and Enolase 1 (ENO1). These findings suggest a link between mitochondrial dysregulation (i.e. high levels of Ndufa4l2), lipid accumulation, and the expression of ccRCC markers ENO1 and CA9, and demonstrate that lipid accumulation and ccRCC development can potentially be attenuated by inhibiting Ndufa4l2.
Language	English
Publishing date	2021-12-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.783856
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Article ; Online: A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes.

Melis, Marta / Tang, Xiao-Han / Attarwala, Nabeel / Chen, Qiuying / Prishker, Carlos / Qin, Lihui / Gross, Steven S / Gudas, Lorraine J / Trasino, Steven E

BioFactors (Oxford, England)

2021 Volume 48, Issue 2, Page(s) 469–480

Abstract: Alcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid ... ...

Abstract	Alcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid metabolism. There are currently no drugs that can both mitigate alcohol-driven hepatic retinoid losses and progression of ALD. Using a mouse model of alcohol intake, we examined if an agonist for the retinoic acid (RA) receptor β2 (RARβ2), AC261066 (AC261) could prevent alcohol-driven hepatic retinoid losses and protect against ALD. Our results show that mice co-treated with AC261 and alcohol displayed mitigation of ALD, including reduced macro, and microvesicular steatosis, and liver damage. Alcohol intake led to increases in hepatic centrilobular levels of ALDH1A1, a rate-limiting enzyme in RA synthesis, and co-localization of ALDH1A1 with the alcohol-metabolizing enzyme CYP2E1, and 4-HNE, a marker of oxidative stress; expression of these targets was abrogated in mice co-treated with AC261 and alcohol. By RNA sequencing technology, we found that AC261 treatments opposed alcohol modulation of 68 transcripts involved in canonical retinoid metabolism. Alcohol modulation of these transcripts, including CES1D, CES1G, RBP1, RDH10, and CYP26A1, collectively favor hepatic retinoid hydrolysis and catabolism. However, despite this, co-administration of AC261 with alcohol did not mitigate alcohol-mediated depletions of hepatic retinoids, but did reduce alcohol-driven increases in serum retinol. Our data show that AC261 protected mice against ALD, even though AC261 did not prevent alcohol-mediated reductions in hepatic retinoids. These data warrant further studies of the anti-ALD properties of AC261.
MeSH term(s)	Lipid Metabolism ; Liver ; Receptors, Retinoic Acid/agonists ; Receptors, Retinoic Acid/genetics ; Receptors, Retinoic Acid/metabolism ; Retinoids/genetics ; Retinoids/metabolism ; Retinoids/pharmacology ; Tretinoin/metabolism ; Tretinoin/pharmacology ; Vitamin A/pharmacology
Chemical Substances	Receptors, Retinoic Acid ; Retinoids ; Vitamin A (11103-57-4) ; Tretinoin (5688UTC01R)
Language	English
Publishing date	2021-10-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	59230-4
ISSN	1872-8081 ; 0951-6433
ISSN (online)	1872-8081
ISSN	0951-6433
DOI	10.1002/biof.1794
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Zs.A 2473: Show issues

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bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Retinoic acid receptor β2 agonists restore glycaemic control in diabetes and reduce steatosis.

Trasino, S E / Tang, X-H / Jessurun, J / Gudas, L J

Diabetes, obesity & metabolism

2016 Volume 18, Issue 2, Page(s) 142–151

Abstract: Aims: To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease.: Methods: Synthetic agonists for RARβ2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 ... ...

Abstract	Aims: To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease. Methods: Synthetic agonists for RARβ2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D). Results: We show that administration of synthetic agonists for RARβ2 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resistance and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase, and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle. Conclusions: Collectively, our data show that orally active, rapid-acting, high-affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis.
MeSH term(s)	Animals ; Benzoates/therapeutic use ; Biphenyl Compounds/therapeutic use ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Diet, High-Fat/adverse effects ; Drugs, Investigational/therapeutic use ; Hyperglycemia/prevention & control ; Hypoglycemic Agents/therapeutic use ; Insulin Resistance ; Kidney/drug effects ; Kidney/metabolism ; Kidney/pathology ; Lipid Peroxidation/drug effects ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Male ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Non-alcoholic Fatty Liver Disease/complications ; Non-alcoholic Fatty Liver Disease/prevention & control ; Obesity/complications ; Oxidative Stress/drug effects ; Pancreas/drug effects ; Pancreas/metabolism ; Pancreas/pathology ; Receptors, Retinoic Acid/agonists ; Receptors, Retinoic Acid/metabolism ; Thiazoles/therapeutic use
Chemical Substances	4'-octyl-4-biphenylcarboxylic acid ; 4-(4-(2-(n-butoxy)ethoxy)-5-methylthiazol-2-yl)-2-fluorobenzoic acid ; Benzoates ; Biphenyl Compounds ; Drugs, Investigational ; Hypoglycemic Agents ; Receptors, Retinoic Acid ; Thiazoles ; retinoic acid receptor beta ; retinoic acid receptor beta2, mouse
Language	English
Publishing date	2016-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.12590
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Zs.A 5442: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article: Clinical and molecular significance of the RNA m

Frontiers in genetics

2023 Volume 13, Page(s) 1096071

Abstract: ... ...

Abstract	N
Language	English
Publishing date	2023-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2022.1096071
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Article: The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer.

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1116424

Abstract: Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, ... ...

Abstract	Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.
Language	English
Publishing date	2023-04-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1116424
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Article: The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer.

Cancers

2022 Volume 14, Issue 20

Abstract: Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing ... ...

Abstract	Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The
Language	English
Publishing date	2022-10-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14205148
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