Systemic hyperosmolality is a severe pathological condition because mammalian cells are not able to tolerate a sustained deviation from osmotic homeostasis. Notable exceptions are renal cells of the kidney inner medulla. These cells utilize mechanisms that allow them to survive, function, and maintain the integrity of their genome during variable and very harsh hyperosmolality. Understanding the molecular basis of such mechanisms provides the knowledge on which to design therapeutic strategies for treating renal diseases and for compensating the pathological effects of systemic hyperosmolality on non-renal cells. We have recently shown that osmotic regulation of DNA repair and chromatin structure represents an important adaptive capacity of renal cells, and that Growth Arrest and DNA Damage inducible genes are induced in renal inner medullary cells exposed to hypertonic stress. Accordingly, our broad objective is to investigate how GADD45 proteins are regulated, in what functional context they are induced, and whether they are necessary for DNA repair and/ or chromatin modulation in renal cells during hypertonic stress. We hypothesize that GADD45 proteins are regulated in various ways in renal inner medullary cells to facilitate cell adaptation to hypertonicity and to protect cells from hypertonicity-induced damage. We will test this hypothesis using the mIMCD3 cell line, primary cultures of rat renal inner medullary cells, and intact animals as models in four aims:
Aim 1 : By investigating how GADD45 proteins are regulated during hypertonic stress;
Aim 2 : By analyzing the effect of hypertonicity on genome integrity in the renal inner medulla in intact animals;
Aim 3 : By testing whether GADD45 proteins are necessary for similar cell functions during hypertonicity as for other types of stress.
Aim 4 : By studying the proteins that are targeted by GADD45 proteins during hypertonic stress in renal inner medullary cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059470-05
Application #
6827376
Study Section
General Medicine B Study Section (GMB)
Program Officer
Mullins, Christopher V
Project Start
2002-03-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
5
Fiscal Year
2005
Total Cost
$235,744
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Park, Eun-Kee; Mak, Sally K; Kultz, Dietmar et al. (2008) Determination of cytotoxicity of nephrotoxins on murine and human kidney cell lines. J Environ Sci Health B 43:71-4
Park, Eun-Kee; Mak, Sally K; Kultz, Dietmar et al. (2007) Evaluation of cytotoxicity attributed to thimerosal on murine and human kidney cells. J Toxicol Environ Health A 70:2092-5
Fiol, Diego F; Mak, Sally K; Kultz, Dietmar (2007) Specific TSC22 domain transcripts are hypertonically induced and alternatively spliced to protect mouse kidney cells during osmotic stress. FEBS J 274:109-24
Valkova, Nelly; Kultz, Dietmar (2006) Constitutive and inducible stress proteins dominate the proteome of the murine inner medullary collecting duct-3 (mIMCD3) cell line. Biochim Biophys Acta 1764:1007-20
Perroud, Bertrand; Lee, Jinoo; Valkova, Nelly et al. (2006) Pathway analysis of kidney cancer using proteomics and metabolic profiling. Mol Cancer 5:64
Pollard, Rachel; Yunis, Reem; Kultz, Dietmar et al. (2006) Ultrasound detection and characterization of polycystic kidney disease in a mouse model. Comp Med 56:215-21
Valkova, Nelly; Yunis, Reem; Mak, Sally K et al. (2005) Nek8 mutation causes overexpression of galectin-1, sorcin, and vimentin and accumulation of the major urinary protein in renal cysts of jck mice. Mol Cell Proteomics 4:1009-18
Kultz, Dietmar (2005) Molecular and evolutionary basis of the cellular stress response. Annu Rev Physiol 67:225-57
Kultz, Dietmar (2005) DNA damage signals facilitate osmotic stress adaptation. Am J Physiol Renal Physiol 289:F504-5
Kultz, Dietmar (2004) Hypertonicity and TonEBP promote development of the renal concentrating system. Am J Physiol Renal Physiol 287:F876-7

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