Diabetic nephropathy (DN) is one of the major complications of diabetes that can lead to end stage renal disease. The rates of DN are escalating and new strategies are needed to combat this debilitating condition. Key features of DN include increased glomerulosclerosis and mesangial cell expansion due to the accumulation of extracellular matrix (ECM) proteins. Although several biochemical pathways and key profibrotic factors, such as transforming growth factor-b1 (TGFb1) and the ECM protein collagen, have been implicated in the pathogenesis of DN, the subtle molecular mechanisms regulating them are unclear. In the previous funding period we identified new roles for renal microRNAs (miRNAs) in the pathogenesis of DN. We demonstrated that miR-192 can mediate TGF b1 induced collagen expression in mesangial cells (MCs), and that miR-192 deficiency can protect against key features of DN in mouse models. Since then, renal miRNAs have gained increased attention in various renal diseases, and are also being recognized as promising clinical biomarkers for DN. However, we still have only limited knowledge about the spectrum of miRNAs that modify DN progression and their therapeutic potential. Our objective is to address this gap in knowledge by identifying the roles of newly identified miRNAs and their host genes in the pathogenesis of DN, and translational approaches to harness their potential to meet the critical need for better therapies for DN. We will follow up on extensive new preliminary data showing that a novel "Mega Cluster" of miRNAs is collectively up-regulated by TGFb1 and high glucose in vitro in MCs, and in diabetic mice glomeruli in vivo. Furthermore, we find that this cluster is embedded within a long transcript and both are regulated by stress responsive transcription factors, whereas target genes of multiple component miRNAs regulate protein translation, hypertrophy and cellular stress. The central hypothesis is that up-regulation of the mega cluster of miRNAs diabetic conditions suppresses the expression of their key functional gene targets, inducing glomerular MC hypertrophy, protein synthesis and fibrosis, and thereby augmenting DN progression. This hypothesis will be tested via three Specific Aims which will: i) examine the molecular mechanisms of regulation of key miRNAs within the mega cluster;ii) identify the functional roles of these miRNAs and key common target genes in MCs, and iii) finally evaluate novel gene targeting as well as translational approaches to down-regulate this miRNA cluster genomic region in mouse models of DN. The results of these conceptually innovative and clinically significant studies can define currently unknown regulatory factors in the diabetic kidney that could lead to the identification of critically needed new therapeutic targets for DN and thus have a positive impact to advance the field.

Public Health Relevance

Diabetes is highly prevalent in the USA and a major healthcare problem especially because it is associated with several debilitating complications. Diabetic nephropathy is one of the major and common complications of both type 1 and type 2 diabetes which can lead to kidney failure as well as painful and costly dialysis. This project proposes to identify novel new mechanisms involved in the progression of diabetic nephropathy that could lead to the development of sorely needed newer biomarkers and therapies to reduce the morbidity and mortality of this diabetic complication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK081705-06
Application #
8772669
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2008-07-01
Project End
2019-05-31
Budget Start
2014-07-10
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$430,598
Indirect Cost
$176,558
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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Castro, Nancy E; Kato, Mitsuo; Park, Jung Tak et al. (2014) Transforming growth factor ?1 (TGF-?1) enhances expression of profibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells. J Biol Chem 289:29001-13
Reddy, Marpadga A; Sumanth, Putta; Lanting, Linda et al. (2014) Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 85:362-73
Leung, Amy; Natarajan, Rama (2014) Noncoding RNAs in vascular disease. Curr Opin Cardiol 29:199-206
Kato, Mitsuo; Castro, Nancy E; Natarajan, Rama (2013) MicroRNAs: potential mediators and biomarkers of diabetic complications. Free Radic Biol Med 64:85-94
Kato, Mitsuo; Dang, Varun; Wang, Mei et al. (2013) TGF-* induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy. Sci Signal 6:ra43
Deshpande, Supriya D; Putta, Sumanth; Wang, Mei et al. (2013) Transforming growth factor-*-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy. Diabetes 62:3151-62
Miao, Feng; Chen, Zhuo; Zhang, Lingxiao et al. (2013) RNA-sequencing analysis of high glucose-treated monocytes reveals novel transcriptome signatures and associated epigenetic profiles. Physiol Genomics 45:287-99
Yuan, Hang; Reddy, Marpadga A; Sun, Guangdong et al. (2013) Involvement of p300/CBP and epigenetic histone acetylation in TGF-?1-mediated gene transcription in mesangial cells. Am J Physiol Renal Physiol 304:F601-13
Park, Jung Tak; Kato, Mitsuo; Yuan, Hang et al. (2013) FOG2 protein down-regulation by transforming growth factor-*1-induced microRNA-200b/c leads to Akt kinase activation and glomerular mesangial hypertrophy related to diabetic nephropathy. J Biol Chem 288:22469-80

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