Diabetic kidney disease (DKD) is a major debilitating complication of diabetes and a significant healthcare problem. Current therapies for DKD are not fully efficacious, with many patients still progressing to renal failure. Inadequate understanding of mechanisms involved in DKD has restricted the development of effective therapies, which underscores the critical need to identify novel mediators and mechanisms leading to DKD. In the previous funding period, we made a significant impact by demonstrating the involvement of non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long ncRNAs (lncRNAs), in the pathogenesis of DKD. We characterized a novel lncRNA, lncMGC, in mesangial cells, which is a host transcript of a mega cluster of miRNAs, the miR-379 cluster. We found that lncMGC modulates critical factors associated with DKD and that a GapmeR antisense oligonucleotide targeting lncMGC ameliorates pathological features of early DKD. However, the molecular and epigenetic mechanisms by which lncMGC promotes features of DKD, the effects of lncMGC, or miR-379 deficiency in vivo on diabetes/obesity-induced renal dysfunction in mice, and sex-specific effects are unclear. The current renewal will address these crucial gaps in knowledge using innovative technologies and mice. The objective of this proposal is to characterize the role of downstream targets and epigenetic regulators of the IncMGC-miR-379 axis in processes that lead to renal dysfunction and DKD. Extensive new preliminary data supporting our research goals include identification of: a) key protein binding partners of lncMGC associated with chromatin remodeling; b) new targets of miR-379 related to DKD pathology; and c) development highly innovative mouse models by CRISPR-Cas9 editing. We hypothesize that diabetes re-programs the mesangial cell (MC) transcriptome and epigenome to dysregulate lncMGC, hosted miR-379, and their key target genes that affect mitochondrial function, oxidative and ER stress resulting in fibrosis, renal dysfunction, and DKD.
Specific Aim 1 will use state-of-the-art Omics profiling and technologies in MCs to determine novel protein targets and epigenetic mechanisms by which the lncMGC-miR-379 axis promotes DKD.
Specific Aim 2 will use novel mouse models of miR-379 and lncMGC deficiency to evaluate the in vivo roles of lncMGC, miR-379, and related critical targets in DKD.
Specific Aim 3 will utilize a novel humanized lncMGC mouse and GapmeR targeting human lncMGC to evaluate the translational potential for human DKD treatment. Because ncRNAs have essential roles in disease states, these continuing studies are both scientifically and clinically significant for DKD research. The project is innovative because it uses cutting edge technologies, novel mouse models, and translational methods. Together, they can alter existing paradigms and have a positive impact by uncovering new ncRNA-mediated regulation of DKD progression, with potentially far-reaching clinical and therapeutic implications, particularly for patients not responding to currently available treatments.

Public Health Relevance

Kidney disease is one of the most common complications of diabetes which can lead to renal failure needing dialysis or transplantation, and is therefore a major healthcare problem. This project will identify novel mechanisms and factors involved in the development of diabetic kidney disease and approaches to target them. The results could lead to much needed newer biomarkers for early detection and therapies to curb the progression of diabetic kidney disease, and thereby reduce mortality in the affected population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK081705-11
Application #
10070017
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Maric-Bilkan, Christine
Project Start
2009-05-01
Project End
2024-06-30
Budget Start
2020-07-21
Budget End
2021-06-30
Support Year
11
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Das, Sadhan; Reddy, Marpadga A; Senapati, Parijat et al. (2018) Diabetes Mellitus-Induced Long Noncoding RNA Dnm3os Regulates Macrophage Functions and Inflammation via Nuclear Mechanisms. Arterioscler Thromb Vasc Biol 38:1806-1820
Leung, Amy; Natarajan, Rama (2018) Long Noncoding RNAs in Diabetes and Diabetic Complications. Antioxid Redox Signal 29:1064-1073
Das, Sadhan; Zhang, Erli; Senapati, Parijat et al. (2018) A Novel Angiotensin II-Induced Long Noncoding RNA Giver Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells. Circ Res 123:1298-1312
Leung, Amy; Amaram, Vishnu; Natarajan, Rama (2018) Linking diabetic vascular complications with LncRNAs. Vascul Pharmacol :
Gangwar, Roopesh S; Rajagopalan, Sanjay; Natarajan, Rama et al. (2018) Noncoding RNAs in Cardiovascular Disease: Pathological Relevance and Emerging Role as Biomarkers and Therapeutics. Am J Hypertens 31:150-165
Das, Sadhan; Senapati, Parijat; Chen, Zhuo et al. (2017) Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells. Nat Commun 8:1467
Kato, Mitsuo; Wang, Mei; Chen, Zhuo et al. (2016) An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat Commun 7:12864
Chen, Zhuo; Miao, Feng; Paterson, Andrew D et al. (2016) Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proc Natl Acad Sci U S A 113:E3002-11
Yuan, Hang; Reddy, Marpadga A; Deshpande, Supriya et al. (2016) Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15-Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy. Antioxid Redox Signal 24:361-75
Bhatt, Kirti; Kato, Mitsuo; Natarajan, Rama (2016) Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 310:F109-18

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