Glucotoxicity, lipotoxicity, advanced glycation end products (AGE), and reactive oxygen species (ROS) have emerged as important mediators of diabetes-induced tissue injury. However, the precise cellular targets and molecular mechanisms by which these mediators cause cellular injury in the kidney remain poorly defined. Both, glomerular (podocytes) and tubular epithelial cells are now emerging as important targets for diabetes-induced injury in diabetic nephropathy (DN). Thus, podocyte depletion has been described recently in humans with type 1 (T1DM) and type 2 (T2DM) diabetes, and is considered a strong predictor for the development of proteinuria. In addition, tubular epithelial apoptosis and epithelial-mesenchymal transition (EMT) may underlie the initiation of tubulointerstitial progression of DN. We present preliminary results that provide a compelling rationale to focus our research program on investigating the emerging role and mechanisms of epithelial cell injury in DN. Specifically, we will test two novel hypotheses: 1. The peroxisomal membrane proteins Mpv17l and/or Mpv17 are essential regulators of antioxidant defenses in glomerular podocytes and protect against diabetes-induced podocyte apoptosis and podocyte depletion (Bottinger, Mount Sinai);and 2. CD36 scavenger receptor for AGE and/or FFA is an essential mediator of AGE and/or FFA-induced tubular epithelial injury/apoptosis and tubulointerstitial progression of DN (Susztak, AECOM).
The Specific Aims of this proposal are to test: 1. whether peroxisomal membrane proteins regulate antioxidant defense mechanisms in podocytes, and protect against ROS-mediated podocyte injury/apoptosis induced by diabetes 2. whether Mpv17-deficiency accelerates and increases podocyte apoptosis and depletion leading to progressive glomerulosclerosis and/or nodules in diabetic mouse models 3. which CD36-dependent intracellular pathways signal AGE and FFA induced tubular epithelial injury/apoptosis 4. whether proximal tubular overexpression of AGE binding proteins CD36 and RAGE leads to increased tubular epithelial injury/apoptosis and tubulointerstitial progression of DN in mice

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01DK060995-10S1
Application #
7896030
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Ketchum, Christian J
Project Start
2009-09-10
Project End
2011-06-30
Budget Start
2009-09-10
Budget End
2011-06-30
Support Year
10
Fiscal Year
2009
Total Cost
$103,687
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Qi, Haiying; Casalena, Gabriella; Shi, Shaolin et al. (2017) Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility. Diabetes 66:763-778
Zhao, Jinghong; Miyamoto, Satoshi; You, Young-Hyun et al. (2015) AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys. Am J Physiol Renal Physiol 308:F1167-77
Declèves, Anne-Emilie; Zolkipli, Zarazuela; Satriano, Joseph et al. (2014) Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int 85:611-23
Sweiss, Natalie; Sharma, Kumar (2014) Adiponectin effects on the kidney. Best Pract Res Clin Endocrinol Metab 28:71-9
Dutta, Dipankar J; Zameer, Andleeb; Mariani, John N et al. (2014) Combinatorial actions of Tgf? and Activin ligands promote oligodendrocyte development and CNS myelination. Development 141:2414-28
Casalena, Gabriela; Krick, Stefanie; Daehn, Ilse et al. (2014) Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro. Am J Physiol Renal Physiol 306:F1372-80
Daehn, Ilse; Casalena, Gabriella; Zhang, Taoran et al. (2014) Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J Clin Invest 124:1608-21
Börgeson, Emma; Sharma, Kumar (2013) Obesity, immunomodulation and chronic kidney disease. Curr Opin Pharmacol 13:618-24
You, Young-Hyun; Okada, Shinichi; Ly, San et al. (2013) Role of Nox2 in diabetic kidney disease. Am J Physiol Renal Physiol 304:F840-8
Shi, Shaolin; Yu, Liping; Zhang, Taoran et al. (2013) Smad2-dependent downregulation of miR-30 is required for TGF-?-induced apoptosis in podocytes. PLoS One 8:e75572

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