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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Rys-Sikora, Krystyna E
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City of Hope/Beckman Research Institute
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Reddy, Marpadga A; Zhang, Erli; Natarajan, Rama (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58:443-55
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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