Kidney disease is increasing at epidemic rates in the US. One clinical sign of kidney disease is protein in the urine (proteinuria). This is typically due to a leak in the normal filtration barrier, and in part is due to injury to a cell called the podocyte. Podocytes are specialized cells that function to limit proteinuria. However, in many diseases including diabetes, podocytes are injured to the point of death, referred to as apoptosis. Moreover, as podocytes die, the remaining podocytes are unable to proliferate and replenish those lost, resulting in a decrease in podocyte number. This further reduces the barrier function of these cells and ultimately leads to kidney failure. The purpose of this grant is to define novel mechanisms underlying podocyte death. Our group has focused in molecules called cell cycle proteins, which reside in the nucleus of the cell. In this grant, we will test the hypothesis that newly discovered cell cycle proteins called cyclin I and cdk5 form a complex which functions to protect podocytes from death in disease. We also believe another partner called p21 adds to this protective function. We will explore possibilities using podocytes in a cell culture system, and also in mice that have been genetically altered to be born without cyclin I, cdk5 and p21. The overall goal is to delineate new paradigms in the regulation of podocyte survival and death, so that ultimately new strategies can be developed to prevent podocyte loss, enhance kidney survival, and reduce kidney disease.

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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Mullins, Christopher V
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Wang, Yuliang; Eng, Diana G; Pippin, Jeffrey W et al. (2018) Sex differences in transcriptomic profiles in aged kidney cells of renin lineage. Aging (Albany NY) 10:606-621
Eng, Diana G; Kaverina, Natalya V; Schneider, Remington R S et al. (2018) Detection of renin lineage cell transdifferentiation to podocytes in the kidney glomerulus with dual lineage tracing. Kidney Int 93:1240-1246
Shankland, Stuart J; Freedman, Benjamin S; Pippin, Jeffrey W (2017) Can podocytes be regenerated in adults? Curr Opin Nephrol Hypertens 26:154-164
Sweetwyne, Mariya T; Pippin, Jeffrey W; Eng, Diana G et al. (2017) The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age. Kidney Int 91:1126-1145
Roeder, Sebastian S; Barnes, Taylor J; Lee, Jonathan S et al. (2017) Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion. Kidney Int 91:896-913
Kaverina, Natalya V; Eng, Diana G; Largent, Andrea D et al. (2017) WT1 Is Necessary for the Proliferation and Migration of Cells of Renin Lineage Following Kidney Podocyte Depletion. Stem Cell Reports 9:1152-1166
McNicholas, Bairbre A; Eng, Diana G; Lichtnekert, Julia et al. (2016) Reducing mTOR augments parietal epithelial cell density in a model of acute podocyte depletion and in aged kidneys. Am J Physiol Renal Physiol 311:F626-39
Lichtnekert, Julia; Kaverina, Natalya V; Eng, Diana G et al. (2016) Renin-Angiotensin-Aldosterone System Inhibition Increases Podocyte Derivation from Cells of Renin Lineage. J Am Soc Nephrol 27:3611-3627
Eng, Diana G; Sunseri, Maria W; Kaverina, Natalya V et al. (2015) Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis. Kidney Int 88:999-1012
Pippin, Jeffrey W; Kaverina, Natalya V; Eng, Diana G et al. (2015) Cells of renin lineage are adult pluripotent progenitors in experimental glomerular disease. Am J Physiol Renal Physiol 309:F341-58

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