Diabetic nephropathy (DN) is one of the major complications of diabetes that can lead to end stage renal disease. Key features of DN include increased glomerulosclerosis and mesangial cell widening due to extracellular matrix (ECM) deposition. Although several biochemical pathways and key profibrotic factors, such as transforming growth factor-beta 1 (TGF-?) and the ECM protein collagen, have been implicated in the pathogenesis of DN, the subtle molecular and nuclear mechanisms regulating them are unclear. We recently uncovered a novel connection between key gene targets of TGF-? in mesangial cells (MCs) and members of a family of small non-coding RNAs called micro-RNAs (miRs). Increasing evidence shows that miRs play important roles in gene regulation since they can suppress the expression of target genes by binding to their mRNAs. Although several targets of miRs have been predicted, much needs to be done to determine their biological and disease relevance. The mechanisms by which miRs are regulated under normal and disease conditions are also not clear. We propose to explore these aspects in the context of DN. We discovered that TGF-? downregulates key repressive factors involved in collagen regulation, and that these factors are also targeted and downregulated by two specific miRs expressed in the kidney and MCs. The expressions of these miRs are increased in MCs treated with TGF-? and also in the glomeruli of diabetic mice. Furthermore, we observed that these miRs can trigger regulatory and feed forward mechanisms that enhance the expression of collagen. We therefore put forward the novel hypothesis that increased TGF-? in DN leads to the aberrant production and actions of key miRs and their target genes which result in enhanced glomerulosclerosis.
Specific Aim 1 will examine the transcriptional mechanisms by which TGF-? upregulates a master miR and its downstream effector miR in MCs.
Specific Aim 2 will evaluate the specific gene target of the downstream miR and how it contributes to TGF-? mediated collagen regulation.
Specific Aim 3 will test the in vivo functional relevance by evaluating the therapeutic potential of anti-miR oligo-nucleotides in diabetic mice, and by examining the progression of DN in a miR knockout mouse. Our preliminary results have uncovered novel hitherto unexplored mechanisms of action of TGF-?. This state-of-the-art study could break new ground and have a major impact in the field of renal research by deciphering the biological functions of these elusive small RNAs in the kidney. They could also pave the way for novel new therapies for diabetic kidney disease.

Public Health Relevance

Diabetes is highly prevalent in the USA and a major healthcare problem. This is further magnified by the fact that it is associated with significantly accelerated and debilitating complications such as diabetic nephropathy. This project proposes to identify novel new mechanisms involved that could lead to the development of sorely needed newer therapies to reduce the morbidity and mortality of diabetic nephropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081705-04
Application #
8287715
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$353,866
Indirect Cost
$140,694
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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
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
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
Reddy, Marpadga A; Natarajan, Rama (2016) Targeting miR-200c to Ameliorate Diabetes-Induced Endothelial Dysfunction. Diabetes 65:1152-4
Oh, Hyung Jung; Kato, Mitsuo; Deshpande, Supriya et al. (2016) Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy. Sci Rep 6:38789
Reddy, Marpadga A; Zhang, Erli; Natarajan, Rama (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58:443-55
Kato, Mitsuo; Natarajan, Rama (2015) MicroRNAs in diabetic nephropathy: functions, biomarkers, and therapeutic targets. Ann N Y Acad Sci 1353:72-88
Schones, Dustin E; Leung, Amy; Natarajan, Rama (2015) Chromatin Modifications Associated With Diabetes and Obesity. Arterioscler Thromb Vasc Biol 35:1557-61
Reddy, Marpadga A; Natarajan, Rama (2015) Recent developments in epigenetics of acute and chronic kidney diseases. Kidney Int 88:250-61
Miao, Feng; Chen, Zhuo; Genuth, Saul et al. (2014) Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes 63:1748-62

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