The renal response to alterations in systemic acid-base balance is complex and involves alterations in membrane transport and intracellular metabolic enzyme activities. One of these changes is an increase in the activity of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK), which occurs as a result of increased gene transcription. The PEPCK gene, although expressed in other tissues, specifically responds to the acid-base state of the whole organism only in the kidney. The goal of this project is the elucidation of mechanisms by which the transcription of a specific gene (PEPCK) is rapidly stimulated in the kidney with metabolic acidosis. Since other genes may be uniquely expressed in kidney in response to metabolic acidosis, study of the properties of this gene as it interacts with the renal epithelial cell milieu may provide insights in the unique renal response as the major organ of external acid-base balance. Flanking areas of genomic DNA surrounding the PEPCK gene have already been shown to confer specificity of expression in response to hormones in renal cells. This study will proceed by using defined regions of the PEPCK gene and flanking DNA to modify the expression of heterologous genes expressed in transfected renal epithelial cell lines and to evaluate the pH responsive properties of this system. In addition, we will seek nuclear binding proteins which interact with the PEPCK gene and may mediate the pH response. The overall goal is a better understanding of the mechanisms of adaptation which accompany renal response to acid-base perturbations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031398-09
Application #
2138616
Study Section
General Medicine B Study Section (GMB)
Project Start
1983-04-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mahimkar, Rajeev M; Visaya, Orvin; Pollock, Allan S et al. (2005) The disintegrin domain of ADAM9: a ligand for multiple beta1 renal integrins. Biochem J 385:461-8
Pollock, Allan S; Turck, Johanna; Lovett, David H (2003) The prodomain of interleukin 1alpha interacts with elements of the RNA processing apparatus and induces apoptosis in malignant cells. FASEB J 17:203-13
Mahimkar, R M; Baricos, W H; Visaya, O et al. (2000) Identification, cellular distribution and potential function of the metalloprotease-disintegrin MDC9 in the kidney. J Am Soc Nephrol 11:595-603
Jabrane-Ferrat, N; Pollock, A S; Goetzl, E J (2000) Inhibition of expression of the type I G protein-coupled receptor for vasoactive intestinal peptide (VPAC1) by hammerhead ribozymes. Biochemistry 39:9771-7
Tanney, D C; Feng, L; Pollock, A S et al. (1998) Regulated expression of matrix metalloproteinases and TIMP in nephrogenesis. Dev Dyn 213:121-9
Mertens, P R; Alfonso-Jaume, M A; Steinmann, K et al. (1998) A synergistic interaction of transcription factors AP2 and YB-1 regulates gelatinase A enhancer-dependent transcription. J Biol Chem 273:32957-65
Turck, J; Pollock, A S; Lovett, D H (1997) Gelatinase A is a glomerular mesangial cell growth and differentiation factor. Kidney Int 51:1397-400
Reddy, D; Pollock, A S; Clark, S A et al. (1997) Transfection and overexpression of the calcium binding protein calbindin-D28k results in a stimulatory effect on insulin synthesis in a rat beta cell line (RIN 1046-38). Proc Natl Acad Sci U S A 94:1961-6
Mertens, P R; Harendza, S; Pollock, A S et al. (1997) Glomerular mesangial cell-specific transactivation of matrix metalloproteinase 2 transcription is mediated by YB-1. J Biol Chem 272:22905-12
Turck, J; Pollock, A S; Lee, L K et al. (1996) Matrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell proliferation and differentiation. J Biol Chem 271:15074-83

Showing the most recent 10 out of 21 publications