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1
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Jo R, Itoh H, Shibata H. Mineralocorticoid receptor overactivation in diabetes mellitus: role of O-GlcNAc modification. Hypertens Res 2024; 47:2126-2132. [PMID: 38789539 DOI: 10.1038/s41440-024-01734-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024]
Abstract
Hypertension is a significant risk factor for microangiopathy and cardiovascular complications in diabetic patients. The efficacy of mineralocorticoid receptor (MR) antagonists in impeding the advancement of diabetic nephropathy, along with the reduction in active renin concentration observed in diabetic retinopathy, strongly implies the involvement of MR overactivation in diabetic complications. This review provides a comprehensive review of various mechanisms proposed for MR overactivation in diabetes mellitus. In particular, it focuses on post-translational MR modifications, including O-linked N-acetylglucosamine modification and phosphorylation, which have been implicated in MR protein stabilization and overactivation under conditions of high glucose. Given the role of MR overactivation in hyperglycemia, it emerges as a promising therapeutic target for preventing diabetic complications. Post-translational modifications (PTMs), such as O-GlcNAcylation and phosphorylation, are related to MR overactivation in diabetes and metabolic syndrome. Aldosterone binding promotes the proteasomal degradation of MR. Under conditions of high glucose, O-GlcNAcylation, and PKCβ-mediated MR phosphorylation are increased. Salt loading and oxidative stress also increase MR phosphorylation through the EGER/ERK pathway. PTMs inhibit ubiquitin attachment to the MR and interfere with the receptor's aldosterone-induced proteasomal degradation. Consequently, they increase the sensitivity of the MR to aldosterone and exacerbate aldosterone-associated complications.
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Affiliation(s)
- Rie Jo
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Keiyu Hospital, Kanagawa, Japan
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Hiroshi Itoh
- Center for Preventive Medicine, Keio University, Tokyo, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan.
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2
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Wu Y, Zou H. Research Progress on Mitochondrial Dysfunction in Diabetic Retinopathy. Antioxidants (Basel) 2022; 11:2250. [PMID: 36421435 PMCID: PMC9686704 DOI: 10.3390/antiox11112250] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/07/2022] [Accepted: 11/12/2022] [Indexed: 09/07/2023] Open
Abstract
Diabetic Retinopathy (DR) is one of the most important microvascular complications of diabetes mellitus, which can lead to blindness in severe cases. Mitochondria are energy-producing organelles in eukaryotic cells, which participate in metabolism and signal transduction, and regulate cell growth, differentiation, aging, and death. Metabolic changes of retinal cells and epigenetic changes of mitochondria-related genes under high glucose can lead to mitochondrial dysfunction and induce mitochondrial pathway apoptosis. In addition, mitophagy and mitochondrial dynamics also change adaptively. These mechanisms may be related to the occurrence and progression of DR, and also provide valuable clues for the prevention and treatment of DR. This article reviews the mechanism of DR induced by mitochondrial dysfunction, and the prospects for related treatment.
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Affiliation(s)
- Yiwei Wu
- Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Haidong Zou
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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3
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Azarova I, Klyosova E, Polonikov A. Association between RAC1 gene variation, redox homeostasis and type 2 diabetes mellitus. Eur J Clin Invest 2022; 52:e13792. [PMID: 35416295 DOI: 10.1111/eci.13792] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/11/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Increased production of reactive oxygen species (ROS) and oxidative stress are known to play a key role in the pathogenesis of type 2 diabetes (T2D); however, the relationship between genes encoding a multi-subunit ROS-generated enzyme NADPH oxidase and disease susceptibility remains unexplored. AIMS The present pilot study investigated whether single-nucleotide polymorphisms (SNP) at the RAC1 gene (Rac family small GTPase 1), a molecular switcher of NADPH oxidase, are associated with the risk of T2D, glucose metabolism and redox homeostasis. MATERIALS & METHODS DNA samples from 3206 unrelated Russian subjects (1579 T2D patients and 1627 controls) were genotyped for six common SNPs rs4724800, rs7784465, rs10951982, rs10238136, rs836478 and rs9374 of RAC1 using the MassArray-4 system. RESULTS SNP rs7784465 was associated with an increased risk of T2D (p = .0003), and significant differences in the RAC1 haplotypes occurred between the cases and controls (p = .005). Seventeen combinations of RAC1 genotypes showed significant associations with T2D risk (FDR <0.05). Associations of RAC1 polymorphisms with T2D were modified by environmental factors such as sedentary lifestyle, psychological stresses, a dietary deficit of fresh fruits/vegetables and increased carbohydrate intake. RAC1 polymorphisms were associated with biochemical parameters in diabetics: rs7784465 (p = .015) and rs836478 (p = .028) with increased glycated haemoglobin, rs836478 (p = .005) with increased fasting blood glucose, oxidized glutathione (p = .012) and uric acid (p = .034). Haplotype rs4724800A-rs7784465C-rs10951982G-rs10238136A-rs836478C-rs9374G was strongly associated with increased levels of hydrogen peroxide (p < .0001). CONCLUSION Thus, polymorphisms in the RAC1 gene represent novel genetic markers of type 2 diabetes, and their link with glucose metabolism and disease pathogenesis is associated with the changes in redox homeostasis.
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Affiliation(s)
- Iuliia Azarova
- Department of Biological Chemistry, Kursk State Medical University, Kursk, Russian Federation.,Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russian Federation
| | - Elena Klyosova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russian Federation
| | - Alexey Polonikov
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.,Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russian Federation
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4
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Sauzeau V, Beignet J, Vergoten G, Bailly C. Overexpressed or hyperactivated Rac1 as a target to treat hepatocellular carcinoma. Pharmacol Res 2022; 179:106220. [PMID: 35405309 DOI: 10.1016/j.phrs.2022.106220] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/31/2022] [Accepted: 04/05/2022] [Indexed: 12/12/2022]
Abstract
Despite novel targeted and immunotherapies, the prognosis remains bleak for patients with hepatocellular carcinoma (HCC), especially for advanced and/or metastatic forms. The rapid emergence of drug resistance is a major obstacle in the success of chemo-, targeted-, immuno-therapies of HCC. Novel targets are needed. The prominent roles of the small GTPase Rac1 in the development and progression of HCC are discussed here, together with its multiple protein partners, and the targeting of Rac1 with RNA-based regulators and small molecules. We discuss the oncogenic functions of Rac1 in HCC, including the contribution of Rac1 mutants and isoform Rac1b. Rac1 is a ubiquitous target, but the protein is frequently overexpressed and hyperactivated in HCC. It contributes to the aggressivity of the disease, with key roles in cancer cell proliferation, tumor metastasis and resistance to treatment. Small molecule targeting Rac1, indirectly or directly, have shown anticancer effects in HCC experimental models. Rac1-binding agents such as EHT 1864 and analogues offer novel opportunities to combat HCC. We discuss the different modalities to repress Rac1 overactivation in HCC with small molecules and the combination with reference drugs to promote cancer cell death and to repress cell invasion. We highlight the necessity to combine Rac1-targeted approach with appropriate biomarkers to select Rac1 activated tumors. Our analysis underlines the prominent oncogenic functions of Rac1 in HCC and discuss the modalities to target this small GTPase. Rac1 shall be considered as a valid target to limit the acquired and intrinsic resistance of HCC tumors and their metastatic potential.
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Affiliation(s)
- Vincent Sauzeau
- Université de Nantes, CHU Nantes, CNRS, INSERM, Institut du Thorax, Nantes, France.
| | - Julien Beignet
- SATT Ouest Valorisation, 30 boulevard Vincent Gâche, CS 70211, 44202 Nantes Cedex, France
| | - Gérard Vergoten
- University of Lille, Inserm, INFINITE - U1286, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculté de Pharmacie, 3 rue du Professeur Laguesse, BP-83, 59006, Lille, France
| | - Christian Bailly
- OncoWitan, Scientific Consulting Office, Lille, Wasquehal 59290, France.
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5
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Kowluru RA. Long Noncoding RNAs and Mitochondrial Homeostasis in the Development of Diabetic Retinopathy. Front Endocrinol (Lausanne) 2022; 13:915031. [PMID: 35733767 PMCID: PMC9207305 DOI: 10.3389/fendo.2022.915031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 04/29/2022] [Indexed: 11/13/2022] Open
Abstract
Retinopathy is one of the most devastating complications of diabetes, which a patient fears the most. Hyperglycemic environment results in many structural, functional, molecular and biochemical abnormalities in the retina, and overproduction of mitochondrial superoxide, induced by hyperglycemic milieu, is considered to play a central role in the development of diabetic retinopathy. Expression of many genes associated with maintaining mitochondrial homeostasis is also altered. Recent research has shown that several long noncoding RNAs, RNAs with more than 200 nucleotides but without any reading frames, are aberrantly expressed in diabetes, and altered expression of these long noncoding RNAs is now being implicated in the development of diabetes and its complications including retinopathy. This review focuses the role of long noncoding RNAs in the development of diabetic retinopathy, with a special emphasis on the maintenance of mitochondrial homeostasis.
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6
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Kowluru RA, Mohammad G. Epigenetic modifications in diabetes. Metabolism 2022; 126:154920. [PMID: 34715117 DOI: 10.1016/j.metabol.2021.154920] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/25/2022]
Abstract
Diabetes is now considered as a 'silent epidemic' that claims over four million lives every year, and the disease knows no socioeconomic boundaries. Despite extensive efforts by the National and International organizations, and cutting-edge research, about 11% world's population is expected to suffer from diabetes (and its complications) by year 2045. This life-long disease damages both the microvasculature and the macrovasculature of the body, and affects many metabolic and molecular pathways, altering the expression of many genes. Recent research has shown that external factors, such as environmental factors, lifestyle and pollutants can also regulate gene expression, and contribute in the disease development and progression. Many epigenetic modifications are implicated in the development of micro- and macro- vascular complications including DNA methylation and histone modifications of several genes implicated in their development. Furthermore, several noncoding RNAs, such as micro RNAs and long noncoding RNAs, are also altered, affecting many biochemical pathways. Epigenetic modifications, however, have the advantage that they could be passed to the next generation, or can be erased. They are now being explored as therapeutical target(s) in the cancer field, which opens up the possibility to use them for treating diabetes and preventing/slowing down its complications.
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Affiliation(s)
- Renu A Kowluru
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, USA.
| | - Ghulam Mohammad
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, USA
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7
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Jiao J, Yu H, Yao L, Li L, Yang X, Liu L. Recent Insights into the Role of Gut Microbiota in Diabetic Retinopathy. J Inflamm Res 2021; 14:6929-6938. [PMID: 34938095 PMCID: PMC8687677 DOI: 10.2147/jir.s336148] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 12/03/2021] [Indexed: 02/06/2023] Open
Abstract
The microbiome has become a hot issue in recent years. The composition, modification, alteration, and disturbance of gut microbiota were found to influence important physiological processes, including energy metabolism and microenvironmental homeostasis, and lead to various diseases, including obesity, type 2 diabetes mellitus and chronic kidney disease. Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus and one of the leading causes of blindness and vision impairment. The underlying mechanisms in DR pathogenesis remain limited. Recently, important insights have been made regarding possible connections between gut microbiome dysbiosis and ocular disease including DR, uveitis, glaucoma, and age-related macular degeneration, and the concept of a "microbiota-gut-retina axis" has been put forward. Hence, we reviewed current understanding of the relationship between DR and gut microbiota. We summarized potential pathophysiological mechanisms that contribute to the role of the gut microbiota on DR, including hyperglycemia, anti-diabetes drugs, microbial metabolites, and inflammatory properties. We aimed to find novel effective therapeutic options to prevent the onset and development of DR.
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Affiliation(s)
- Jinghua Jiao
- Department of Anesthesiology, Central Hospital, Shenyang Medical College, Shenyang, Liaoning, 110024, People's Republic of China
| | - Honghua Yu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510120, People's Republic of China
| | - Litong Yao
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Lihua Li
- Department of Ophthalmology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, 261031, People's Republic of China
| | - Xiaohong Yang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510120, People's Republic of China
| | - Lei Liu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510120, People's Republic of China
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8
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Kern TS, Du Y, Tang J, Lee CA, Liu H, Dreffs A, Leinonen H, Antonetti DA, Palczewski K. Regulation of Adrenergic, Serotonin, and Dopamine Receptors to Inhibit Diabetic Retinopathy: Monotherapies versus Combination Therapies. Mol Pharmacol 2021; 100:470-479. [PMID: 34393108 PMCID: PMC9175131 DOI: 10.1124/molpharm.121.000278] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 08/03/2021] [Indexed: 11/22/2022] Open
Abstract
We compared monotherapies and combinations of therapies that regulate G-protein-coupled receptors (GPCRs) with respect to their abilities to inhibit early stages of diabetic retinopathy (DR) in streptozotocin-diabetic mice. Metoprolol (MTP; 0.04-1.0 mg/kg b.wt./day), bromocriptine (BRM; 0.01-0.1 mg/kg b.wt./day), doxazosin (DOX; 0.01-1.0 mg/kg b.wt./day), or tamsulosin (TAM; 0.05-0.25 mg/kg b.wt./day) were injected individually daily for 2 months in dose-response studies to assess their effects on the diabetes-induced increases in retinal superoxide and leukocyte-mediated cytotoxicity against vascular endothelial cells, both of which abnormalities have been implicated in the development of DR. Each of the individual drugs inhibited the diabetes-induced increase in retinal superoxide at the higher concentrations tested, but the inhibition was lost at lower doses. To determine whether combination therapies had superior effects over individual drugs, we intentionally selected for each drug a low dose that had little or no effect on the diabetes-induced retinal superoxide for use separately or in combinations in 8-month studies of retinal function, vascular permeability, and capillary degeneration in diabetes. At the low doses used, combinations of the drugs generally were more effective than individual drugs, but the low-dose MTP alone totally inhibited diabetes-induced reduction in a vision task, BRM or DOX alone totally inhibited the vascular permeability defect, and DOX alone totally inhibited diabetes-induced degeneration of retinal capillaries. Although low-dose MTP, BRM, DOX, or TAM individually had beneficial effects on some endpoints, combination of the therapies better inhibited the spectrum of DR lesions evaluated. SIGNIFICANCE STATEMENT: The pathogenesis of early stages of diabetic retinopathy remains incompletely understood, but multiple different cell types are believed to be involved in the pathogenic process. We have compared the effects of monotherapies to those of combinations of drugs that regulate GPCR signaling pathways with respect to their relative abilities to inhibit the development of early diabetic retinopathy.
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Affiliation(s)
- Timothy S Kern
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - Yunpeng Du
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - Jie Tang
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - Chieh Allen Lee
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - Haitao Liu
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - Alyssa Dreffs
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - Henri Leinonen
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - David A Antonetti
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
| | - Krzysztof Palczewski
- Center for Translational Vision Research, Gavin Herbert Eye Institute (T.S.K., Y.D., H.L., K.P.), Department of Physiology and Biophysics (K.P.), and Department of Chemistry (K.P.), University of California-Irvine, Irvine, California; Veterans Administration Medical Center, Long Beach Healthcare System, Research Service, Long Beach, California (T.S.K.); Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio (J.T., C.A.L.); and Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan (A.D., D.A.A.)
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9
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Rodríguez ML, Millán I, Ortega ÁL. Cellular targets in diabetic retinopathy therapy. World J Diabetes 2021; 12:1442-1462. [PMID: 34630899 PMCID: PMC8472497 DOI: 10.4239/wjd.v12.i9.1442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/08/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the existence of treatment for diabetes, inadequate metabolic control triggers the appearance of chronic complications such as diabetic retinopathy. Diabetic retinopathy is considered a multifactorial disease of complex etiology in which oxidative stress and low chronic inflammation play essential roles. Chronic exposure to hyperglycemia triggers a loss of redox balance that is critical for the appearance of neuronal and vascular damage during the development and progression of the disease. Current therapies for the treatment of diabetic retinopathy are used in advanced stages of the disease and are unable to reverse the retinal damage induced by hyperglycemia. The lack of effective therapies without side effects means there is an urgent need to identify an early action capable of preventing the development of the disease and its pathophysiological consequences in order to avoid loss of vision associated with diabetic retinopathy. Therefore, in this review we propose different therapeutic targets related to the modulation of the redox and inflammatory status that, potentially, can prevent the development and progression of the disease.
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Affiliation(s)
- María Lucía Rodríguez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
| | - Iván Millán
- Neonatal Research Group, Health Research Institute La Fe, Valencia 46026, Valencia, Spain
| | - Ángel Luis Ortega
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
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10
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Kowluru RA, Radhakrishnan R, Mohammad G. Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy. Sci Rep 2021; 11:14097. [PMID: 34238980 PMCID: PMC8266843 DOI: 10.1038/s41598-021-93420-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/17/2021] [Indexed: 12/16/2022] Open
Abstract
Cytosolic ROS, generated by NADPH oxidase 2 (Nox2) in diabetes, damage retinal mitochondria, which leads to the development of retinopathy. A small molecular weight G-protein essential for Nox2 activation, Rac1, is also transcriptionally activated via active DNA methylation-hydroxymethylation. DNA methylation is a dynamic process, and can also be regulated by histone modifications; diabetes alters retinal histone methylation machinery. Our aim is to investigate the role of histone methylation (H3K9me3) of Rac1 promoter in dynamic DNA methylation- transcriptional activation. Using human retinal endothelial cells in 20 mM D-glucose, H3K9me3 at Rac1 promoter was quantified by chromatin-Immunoprecipitation technique. Crosstalk between H3K9me3 and DNA methylation was examined in cells transfected with siRNA of histone trimethyl-transferase, Suv39H1, or Dnmt1, exposed to high glucose. Key parameters were confirmed in retinal microvessels from streptozotocin-induced diabetic mice, with intravitreally administered Suv39H1-siRNA or Dnmt1-siRNA. Compared to cells in normal glucose, high glucose increased H3K9me3 and Suv39H1 binding at Rac1 promoter, and Suv39H1-siRNA prevented glucose-induced increase 5 hydroxy methyl cytosine (5hmC) and Rac1 mRNA. Similarly, in diabetic mice, Suv39H1-siRNA attenuated increase in 5hmC and Rac1 mRNA. Thus, H3K9me3 at Rac1 promoter assists in active DNA methylation-hydroxymethylation, activating Rac1 transcription. Regulation of Suv39H1-H3K9 trimethylation could prevent further epigenetic modifications, and prevent diabetic retinopathy.
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Affiliation(s)
- Renu A Kowluru
- Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI, 48201, USA.
| | - Rakesh Radhakrishnan
- Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Ghulam Mohammad
- Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI, 48201, USA
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11
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Gendaszewska-Darmach E, Garstka MA, Błażewska KM. Targeting Small GTPases and Their Prenylation in Diabetes Mellitus. J Med Chem 2021; 64:9677-9710. [PMID: 34236862 PMCID: PMC8389838 DOI: 10.1021/acs.jmedchem.1c00410] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
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A fundamental role
of pancreatic β-cells to maintain proper
blood glucose level is controlled by the Ras superfamily of small
GTPases that undergo post-translational modifications, including prenylation.
This covalent attachment with either a farnesyl or a geranylgeranyl
group controls their localization, activity, and protein–protein
interactions. Small GTPases are critical in maintaining glucose homeostasis
acting in the pancreas and metabolically active tissues such as skeletal
muscles, liver, or adipocytes. Hyperglycemia-induced upregulation
of small GTPases suggests that inhibition of these pathways deserves
to be considered as a potential therapeutic approach in treating T2D.
This Perspective presents how inhibition of various points in the
mevalonate pathway might affect protein prenylation and functioning
of diabetes-affected tissues and contribute to chronic inflammation
involved in diabetes mellitus (T2D) development. We also demonstrate
the currently available molecular tools to decipher the mechanisms
linking the mevalonate pathway’s enzymes and GTPases with diabetes.
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Affiliation(s)
- Edyta Gendaszewska-Darmach
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego Street 4/10, 90-924 Łódź, Poland
| | - Malgorzata A Garstka
- Core Research Laboratory, Department of Endocrinology, Department of Tumor and Immunology, Precision Medical Institute, Western China Science and Technology Innovation Port, School of Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, DaMingGong, Jian Qiang Road, Wei Yang district, Xi'an 710016, China
| | - Katarzyna M Błażewska
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego Street 116, 90-924 Łódź, Poland
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12
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Tonade D, Kern TS. Photoreceptor cells and RPE contribute to the development of diabetic retinopathy. Prog Retin Eye Res 2021; 83:100919. [PMID: 33188897 PMCID: PMC8113320 DOI: 10.1016/j.preteyeres.2020.100919] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/27/2020] [Accepted: 10/31/2020] [Indexed: 12/26/2022]
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the neural retina. Unfortunately, research on the vascular and neural abnormalities have remained largely separate, instead of being integrated into a comprehensive view of DR that includes both the neural and vascular components. Recent evidence suggests that the most predominant neural cell in the retina (photoreceptors) and the adjacent retinal pigment epithelium (RPE) play an important role in the development of vascular lesions characteristic of DR. This review summarizes evidence that the outer retina is altered in diabetes, and that photoreceptors and RPE contribute to retinal vascular alterations in the early stages of the retinopathy. The possible molecular mechanisms by which cells of the outer retina might contribute to retinal vascular damage in diabetes also are discussed. Diabetes-induced alterations in the outer retina represent a novel therapeutic target to inhibit DR.
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Affiliation(s)
- Deoye Tonade
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA
| | - Timothy S Kern
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA; Veterans Administration Medical Center Research Service, Cleveland, OH, USA; Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, USA; Veterans Administration Medical Center Research Service, Long Beach, CA, USA.
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13
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Ying C, Dai J, Fan G, Zhou Z, Gan T, Zhang Y, Song Y, Zhou X. Ras-Related C3 Botulinum Toxin Substrate 1 Combining With the Mixed Lineage Kinase 3- Mitogen-Activated Protein Kinase 7- c-Jun N-Terminal Kinase Signaling Module Accelerates Diabetic Nephropathy. Front Physiol 2021; 12:679166. [PMID: 34194338 PMCID: PMC8236718 DOI: 10.3389/fphys.2021.679166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022] Open
Abstract
Ras-related C3 botulinum toxin substrate 1 (RAC1) activation plays a vital role in diabetic nephropathy (DN), but the exact mechanism remains unclear. In this study, we attempted to elucidate the precise mechanism of how RAC1 aggravates DN through cellular and animal experiments. In this study, DN was induced in mice by intraperitoneal injection of streptozotocin (STZ, 150mg/kg), and the RAC1 inhibitor NSC23766 was administered by tail vein injection. Biochemical indicators, cell proliferation and apoptosis, and morphological changes in the kidney were detected. The expression of phosphorylated c-Jun N-terminal kinase (p-JNK), nuclear factor-κB (NF-κB), and cleaved caspase-3 and the interaction between RAC1 and the mixed lineage kinase 3 (MLK3)-mitogen-activated protein kinase 7 (MKK7)-JNK signaling module were determined. Furthermore, the colocalization and direct co-interaction of RAC1 and MLK3 were confirmed. Our results showed that RAC1 accelerates renal damage and increases the expression of p-JNK, NF-κB, and cleaved caspase-3. However, inhibition of RAC1 ameliorated DN by downregulating p-JNK, NF-κB, and cleaved caspase-3. Also, RAC1 promoted the assembly of MLK3-MKK7-JNK, and NSC23766 blocked the interaction between RAC1 and MLK3-MKK7-JNK and inhibited the assembly of the MLK3-MKK7-JNK signaling module. Furthermore, RAC1 was combined with MLK3 directly, but the RAC1 Y40C mutant inhibited the interaction between RAC1 and MLK3. We demonstrated that RAC1 combining with MLK3 activates the MLK3-MKK7-JNK signaling module, accelerating DN occurrence and development, and RAC1 Y40 is an important site for binding of RAC1 to MLK3. This study illustrates the cellular and molecular mechanisms of how RAC1 accelerates DN and provides evidence of DN-targeted therapy.
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Affiliation(s)
- Changjiang Ying
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jiao Dai
- The Graduate School, Xuzhou Medical University, Xuzhou, China
| | - Gaoxia Fan
- The Graduate School, Xuzhou Medical University, Xuzhou, China
| | - Zhongyuan Zhou
- The Graduate School, Xuzhou Medical University, Xuzhou, China
| | - Tian Gan
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yusheng Zhang
- The Graduate School, Xuzhou Medical University, Xuzhou, China
| | - Yuanjian Song
- Department of Genetics, School of Life Sciences, Xuzhou Medical University, Xuzhou, China
| | - Xiaoyan Zhou
- Department of Genetics, School of Life Sciences, Xuzhou Medical University, Xuzhou, China
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14
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Xie N, Meng Q, Zhang Y, Luo Z, Xue F, Liu S, Li Y, Huang Y. MicroRNA‑142‑3p suppresses cell proliferation, invasion and epithelial‑to‑mesenchymal transition via RAC1‑ERK1/2 signaling in colorectal cancer. Mol Med Rep 2021; 24:568. [PMID: 34109430 PMCID: PMC8201444 DOI: 10.3892/mmr.2021.12207] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/13/2021] [Indexed: 12/24/2022] Open
Abstract
Aberrant expression of microRNAs (miRNAs/miRs) is associated with the initiation and progression of colorectal cancer (CRC), but how they regulate colorectal tumorigenesis is still unknown. The present study was designed to investigate the expression profile of miRNAs in human CRC tissues, and to reveal the molecular mechanism of miRNA-142-3p in suppressing colon cancer cell proliferation. The expression of miRNA was examined using an Exiqon miRNA array. Bioinformatics was used to predict the target genes of differentially expressed miRNAs and to analyze their biological function in CRC. The effect of miR-142-3p in colon cancer cells was evaluated in vitro using cell proliferation, colony formation and Transwell assays. Dual-luciferase reporter gene assays were performed to investigate the association between miR-142-3p and Rac family small GTPase 1 (RAC1). The effect of miR-142-3p regulation on colon cancer proliferation was assessed through western blotting and quantitative polymerase chain reaction analysis. Compared with their expression in adjacent non-cancer mucosal tissues, 76 miRNAs were upregulated and 102 miRNAs were downregulated in CRC. One of the most significantly and differentially regulated miRNAs was miR-142-3p, which was downregulated in 81.0% (51/63) of primary CRC tissues. After transfection of miR-142-3p mimics into colon cancer cells, proliferation and colony formation were decreased, and migration and invasion were markedly suppressed. RAC1 was a possible target of miR-142-3p, which was confirmed by dual-luciferase reporter assay. Transfection of miR-142-3p mimics decreased the levels of RAC1 and suppressed epithelial-to-mesenchymal transition in colon cancer cells. The phosphorylation of extraceullar signal-regulated kinase (ERK) was decreased significantly by the inhibition of RAC1 or transfection of miR-142-3p mimics in colon cancer cells. In conclusion, aberrant miRNAs are implicated in CRC. Decreased expression of miR-142-3p may be associated with CRC tumorigenesis via Rac1-ERK signaling.
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Affiliation(s)
- Na Xie
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Qiuping Meng
- Department of Pathology, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Yixin Zhang
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Zhifei Luo
- Department of Pathology, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Fenggui Xue
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Sisi Liu
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Ying Li
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Yousheng Huang
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
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15
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Kowluru RA. Diabetic Retinopathy and NADPH Oxidase-2: A Sweet Slippery Road. Antioxidants (Basel) 2021; 10:783. [PMID: 34063353 PMCID: PMC8156589 DOI: 10.3390/antiox10050783] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/03/2021] [Accepted: 05/13/2021] [Indexed: 11/17/2022] Open
Abstract
Diabetic retinopathy remains the leading cause of vision loss in working-age adults. The multi-factorial nature of the disease, along with the complex structure of the retina, have hindered in elucidating the exact molecular mechanism(s) of this blinding disease. Oxidative stress appears to play a significant role in its development and experimental models have shown that an increase in cytosolic Reacttive Oxygen Speies (ROS) due to the activation of NADPH oxidase 2 (Nox2), is an early event, which damages the mitochondria, accelerating loss of capillary cells. One of the integral proteins in the assembly of Nox2 holoenzyme, Rac1, is also activated in diabetes, and due to epigenetic modifications its gene transcripts are upregulated. Moreover, addition of hyperlipidemia in a hyperglycemic milieu (type 2 diabetes) further exacerbates Rac1-Nox2-ROS activation, and with time, this accelerates and worsens the mitochondrial damage, ultimately leading to the accelerated capillary cell loss and the development of diabetic retinopathy. Nox2, a multicomponent enzyme, is a good candidate to target for therapeutic interventions, and the inhibitors of Nox2 and Rac1 (and its regulators) are in experimental or clinical trials for other diseases; their possible use to prevent/halt retinopathy will be a welcoming sign for diabetic patients.
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Affiliation(s)
- Renu A Kowluru
- Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA
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16
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Lv J, Liu Y, Cui J, Fang H, Wu Y, Zhu X, Guo M, Li C, Dou J, Chen Z, Du X. Profile Screening of Differentially Expressed lncRNAs of Circulating Leukocytes in Type 2 Diabetes Patients and Differences From Type 1 Diabetes. Front Endocrinol (Lausanne) 2021; 12:690555. [PMID: 35082751 PMCID: PMC8786112 DOI: 10.3389/fendo.2021.690555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 12/13/2021] [Indexed: 11/15/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) have been reported to have multiple functions and can be used as markers of various diseases, including diabetes. This study was conducted to determine the lncRNA profile in leukocytes from patients with type 2 diabetes (T2D). Differential expression of lncRNAs in T2D and type 1 diabetes (T1D) was also examined. RNA sequencing was performed in a critically grouped sample of leukocytes from T2D patients and healthy persons. A total of 845 significantly differentially expressed lncRNAs were identified, with 260 downregulated and 585 upregulated lncRNAs in T2D. The analysis of functions of DE-lncRNA and constructed co-expression networks (CNC) showed that 21 lncRNAs and 117 mRNAs harbored more than 10 related genes in CNC. Fourteen of 21 lncRNAs were confirmed to be significantly differentially expressed was detected by qPCR between the T2D and control validation cohorts. We also identified a panel of 4 lncRNAs showing significant differences in expression between T1D and T2D. Collectively, hundreds of novel DE-lncRNAs we identified in leukocytes from T2D patients will aid in epigenetic mechanism studies. Fourteen confirmed DE-lncRNAs can be regarded as diagnostic markers or regulators of T2D, including 4 lncRNAs that chould distinguish T1D and T2D in clinical practice to avoid misdiagnosis.
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Affiliation(s)
- Jianyi Lv
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yihan Liu
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jia Cui
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Hongjuan Fang
- Department of Endocrinology, Beijing TianTan Hospital, Capital Medical University, Beijing, China
| | - Ying Wu
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiao Zhu
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Meng Guo
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jingtao Dou
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Xiaoyan Du,
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17
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Maltas J, Reed H, Porter A, Malliri A. Mechanisms and consequences of dysregulation of the Tiam family of Rac activators in disease. Biochem Soc Trans 2020; 48:2703-2719. [PMID: 33200195 DOI: 10.1042/bst20200481] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 12/14/2022]
Abstract
The Tiam family proteins - Tiam1 and Tiam2/STEF - are Rac1-specific Guanine Nucleotide Exchange Factors (GEFs) with important functions in epithelial, neuronal, immune and other cell types. Tiam GEFs regulate cellular migration, proliferation and survival, mainly through activating and directing Rac1 signalling. Dysregulation of the Tiam GEFs is significantly associated with human diseases including cancer, immunological and neurological disorders. Uncovering the mechanisms and consequences of dysregulation is therefore imperative to improving the diagnosis and treatment of diseases. Here we compare and contrast the subcellular localisation and function of Tiam1 and Tiam2/STEF, and review the evidence for their dysregulation in disease.
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Affiliation(s)
- Joe Maltas
- Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, U.K
| | - Hannah Reed
- Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, U.K
| | - Andrew Porter
- Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, U.K
| | - Angeliki Malliri
- Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, U.K
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18
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Diabetic Retinopathy: Mitochondria Caught in a Muddle of Homocysteine. J Clin Med 2020; 9:jcm9093019. [PMID: 32961662 PMCID: PMC7564979 DOI: 10.3390/jcm9093019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/09/2020] [Accepted: 09/17/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic retinopathy is one of the most feared complications of diabetes. In addition to the severity of hyperglycemia, systemic factors also play an important role in its development. Another risk factor in the development of diabetic retinopathy is elevated levels of homocysteine, a non-protein amino acid, and hyperglycemia and homocysteine are shown to produce synergistic detrimental effects on the vasculature. Hyperhomocysteinemia is associated with increased oxidative stress, and in the pathogenesis of diabetic retinopathy, oxidative stress-mitochondrial dysfunction precedes the development of histopathology characteristic of diabetic retinopathy. Furthermore, homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), and SAM is a co-substrate of DNA methylation. In diabetes, DNA methylation machinery is activated, and mitochondrial DNA (mtDNA) and several genes associated with mitochondrial homeostasis undergo epigenetic modifications. Consequently, high homocysteine, by further affecting methylation of mtDNA and that of genes associated with mtDNA damage and biogenesis, does not give any break to the already damaged mitochondria, and the vicious cycle of free radicals continues. Thus, supplementation of sensible glycemic control with therapies targeting hyperhomocysteinemia could be valuable for diabetic patients to prevent/slow down the development of this sight-threatening disease.
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19
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Kowluru A. Roles of GTP and Rho GTPases in pancreatic islet beta cell function and dysfunction. Small GTPases 2020; 12:323-335. [PMID: 32867592 DOI: 10.1080/21541248.2020.1815508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A growing body of evidence implicates requisite roles for GTP and its binding proteins (Rho GTPases) in the cascade of events leading to physiological insulin secretion from the islet beta cell. Interestingly, chronic exposure of these cells to hyperglycaemic conditions appears to result in sustained activation of specific Rho GTPases (e.g. Rac1) leading to significant alterations in cellular functions including defects in mitochondrial function and nuclear collapse culminating in beta cell demise. One of the objectives of this review is to highlight our current understanding of the regulatory roles of GTP and Rho GTPases in normal islet function (e.g. proliferation and insulin secretion) as well potential defects in these signalling molecules and metabolic pathways that could contribute islet beta cell dysfunction and loss of functional beta cell mass leading to the onset of diabetes. Potential knowledge gaps in this field and possible avenues for future research are also highlighted. ABBREVIATIONS ARNO: ADP-ribosylation factor nucleotide binding site opener; CML: carboxyl methylation; Epac: exchange protein directly activated by cAMP; ER stress: endoplasmic reticulum stress; FTase: farnesyltransferase; GAP: GTPase activating protein; GDI: GDP dissociation inhibitor; GEF: guanine nucleotide exchange factor; GGTase: geranylgeranyltransferase; GGpp: geranylgeranylpyrophosphate; GGPPS: geranylgeranyl pyrophosphate synthase; GSIS: glucose-stimulated insulin secretion; HGPRTase: hypoxanthine-guanine phosphoribosyltransferase; IMPDH: inosine monophosphate dehydrogenase; α-KIC: α-ketoisocaproic acid; MPA: mycophenolic acid; MVA: mevalonic acid; NDPK: nucleoside diphosphate kinase; NMPK: nucleoside monophosphate kinase; Nox2: phagocyte-like NADPH oxidase; PAK-I: p21-activated kinase-I; β-PIX: β-Pak-interacting exchange factor; PRMT: protein arginine methyltransferase; Rac1: ras-related C3 botulinum toxin substrate 1; Tiam1: T-cell lymphoma invasion and metastasis-inducing protein 1; Trx-1: thioredoxin-1; Vav2: vav guanine nucleotide exchange factor 2.
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Affiliation(s)
- Anjaneyulu Kowluru
- Biomedical Research Service, John D. Dingell VA Medical Center and Department of Pharmaceutical Sciences and Medicine, Wayne State University, Detroit, MI, USA
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20
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Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies. Antioxidants (Basel) 2020; 9:antiox9080761. [PMID: 32824523 PMCID: PMC7465265 DOI: 10.3390/antiox9080761] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/11/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Abstract
Many retinal diseases, such as diabetic retinopathy, glaucoma, and age-related macular (AMD) degeneration, are associated with elevated reactive oxygen species (ROS) levels. ROS are important intracellular signaling molecules that regulate numerous physiological actions, including vascular reactivity and neuron function. However, excessive ROS formation has been linked to vascular endothelial dysfunction, neuron degeneration, and inflammation in the retina. ROS can directly modify cellular molecules and impair their function. Moreover, ROS can stimulate the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) causing inflammation and cell death. However, there are various compounds with direct or indirect antioxidant activity that have been used to reduce ROS accumulation in animal models and humans. In this review, we report on the physiological and pathophysiological role of ROS in the retina with a special focus on the vascular system. Moreover, we present therapeutic approaches for individual retinal diseases targeting retinal signaling pathways involving ROS.
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21
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Kowluru RA. Retinopathy in a Diet-Induced Type 2 Diabetic Rat Model and Role of Epigenetic Modifications. Diabetes 2020; 69:689-698. [PMID: 31949005 PMCID: PMC7085254 DOI: 10.2337/db19-1009] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 01/08/2020] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes accounts for 90% of the population with diabetes, and these patients are generally obese and hyperlipidemic. In addition to hyperglycemia, hyperlipidemia is also closely related with diabetic retinopathy. The aim was to investigate retinopathy in a model closely mimicking the normal progression and metabolic features of the population with type 2 diabetes and elucidate the molecular mechanism. Retinopathy was evaluated in rats fed a 45% kcal as fat diet for 8 weeks before administering streptozotocin, 30 mg/kg body weight (T2D), and compared with age- and duration-matched type 1 diabetic rats (T1D) (60 mg/kg streptozotocin). The role of epigenetic modifications in mitochondrial damage was evaluated in retinal microvasculature. T2D rats were obese and severely hyperlipidemic, with impaired glucose and insulin tolerance compared with age-matched T1D rats. While at 4 months of diabetes, T1D rats had no detectable retinopathy, T2D rats had significant retinopathy, their mitochondrial copy numbers were lower, and mtDNA and Rac1 promoter DNA methylation was exacerbated. At 6 months, retinopathy was comparable in T2D and T1D rats, suggesting that obesity exaggerates hyperglycemia-induced epigenetic modifications, accelerating mitochondrial damage and diabetic retinopathy. Thus, maintenance of good lifestyle and BMI could be beneficial in regulating epigenetic modifications and preventing/retarding retinopathy in patients with diabetes.
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MESH Headings
- Animals
- DNA Methylation
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 2/etiology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetic Retinopathy/genetics
- Diabetic Retinopathy/metabolism
- Diet, High-Fat/adverse effects
- Disease Models, Animal
- Epigenesis, Genetic
- Insulin Resistance/physiology
- Male
- Promoter Regions, Genetic
- Rats
- Rats, Sprague-Dawley
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Affiliation(s)
- Renu A Kowluru
- Kresge Eye Institute, Wayne State University, Detroit, MI
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22
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Abstract
Glucose-induced (physiological) insulin secretion from the islet β-cell involves interplay between cationic (i.e., changes in intracellular calcium) and metabolic (i.e., generation of hydrophobic and hydrophilic second messengers) events. A large body of evidence affirms support for novel regulation, by G proteins, of specific intracellular signaling events, including actin cytoskeletal remodeling, transport of insulin-containing granules to the plasma membrane for fusion, and secretion of insulin into the circulation. This article highlights the following aspects of GPCR-G protein biology of the islet. First, it overviews our current understanding of the identity of a wide variety of G protein regulators and their modulatory roles in GPCR-G protein-effector coupling, which is requisite for optimal β-cell function under physiological conditions. Second, it describes evidence in support of novel, noncanonical, GPCR-independent mechanisms of activation of G proteins in the islet. Third, it highlights the evidence indicating that abnormalities in G protein function lead to islet β-cell dysregulation and demise under the duress of metabolic stress and diabetes. Fourth, it summarizes observations of potential beneficial effects of GPCR agonists in preventing/halting metabolic defects in the islet β-cell under various pathological conditions (e.g., metabolic stress and inflammation). Lastly, it identifies knowledge gaps and potential avenues for future research in this evolving field of translational islet biology. Published 2020. Compr Physiol 10:453-490, 2020.
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Affiliation(s)
- Anjaneyulu Kowluru
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Center for Translational Research in Diabetes, Biomedical Research Service, John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, USA
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