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Signal Transduction in Diabetic Nephropathy

Simonson, Michael Scott
http://rave.ohiolink.edu/etdc/view?acc_num=case1343145610

Abstract Details

2012, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Kidney disease in diabetes, or diabetic nephropathy, is the most prevalent cause of end-stage renal failure worldwide. Available therapy does not prevent onset of nephropathy or end-stage renal disease. We inferred dysregulation of signal transduction in diabetic nephropathy by profiling the renal transcriptome of 8 and 16 week db/m control and db/db type 2 diabetic mice. The data suggested that autocrine signaling by endothelin-1 (ET-1) was increased in 8-week db/db kidney, followed at 16 weeks by elevated expression of 16 diverse autocrine factors including transforming growth factor beta (TGFbeta), growth and differentiation factor 15 (GDF15), macrophage chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and lipocalin-2 (LCN2). The majority of these autocrine factors have not been associated previously with diabetic nephropathy. The stimulated autocrine signaling network at 16 weeks correlated temporally with hypertrophy, expansion of mesangial matrix and atrophy of proximal tubules. Bioinformatic enrichment analysis suggested that elevated secretion of ET-1 may evoke autocrine cytokine- and chemokine-based signaling. Experiments in human mesangial cells supported this hypothesis. Exogenous ET-1 induced secretion of IL-6 and MCP-1, which in turn increased collagen production by an autocrine feedforward signaling loop. In a comparative study of humans with type 2 diabetes, urine levels of ET-1, TGFbeta, GDF15, MCP-1, IL-6 and LCN2 were elevated compared to age-matched non-diabetic controls. Urine levels of the six autocrine signals correlated inversely with estimated glomerular filtration rate, and ET-1, GDF15 and IL-6 correlated positively with a marker of proximal tubule injury, urine N-acetyl-beta-D-glucosaminidase. Taken together, these results suggest that in mice and humans with type 2 diabetic nephropathy increased autocrine signaling activity in the kidney is conserved. Furthermore, increased secretion of ET-1 may induce a feedforward autocrine loop involving pro-inflammatory chemokines and cytokines.
Faramarz Ismail-Beigi, MD, PhD (Advisor)
William Schilling, PhD (Committee Chair)
Ulrich Hopfer, MD, PhD (Committee Member)
Andrea Romani, MD, PhD (Committee Member)
Timothy Kern, PhD (Committee Member)
Stephen Jones, PhD (Committee Member)
96 p.
Physiology
diabetic nephropathy; signal transduction; endothelin-1; computational biology

Recommended Citations

Citations

  • Simonson, M. S. (2012). Signal Transduction in Diabetic Nephropathy [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1343145610

    APA Style (7th edition)

  • Simonson, Michael. Signal Transduction in Diabetic Nephropathy. 2012. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1343145610.

    MLA Style (8th edition)

  • Simonson, Michael. "Signal Transduction in Diabetic Nephropathy." Doctoral dissertation, Case Western Reserve University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1343145610

    Chicago Manual of Style (17th edition)

case1343145610
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© 2012, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12