HETEROGENEITY OF RENAL PEPTIDE TRANSPORTERS

肾肽转运蛋白的异质性

• 批准号: 2749831
• 负责人: DAVID E SMITH
• 金额: $ 18.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749831
• 关键词: Xenopus oocyte; aminoacid transport; brush border membrane; immunologic assay /test; laboratory rat; membrane transport proteins; oligopeptides; protein isoforms; protein structure function; renal cortex; renal medulla; renal tubular transport; vesicle /vacuole

Specialized transporters, such as the renal peptide transport system, play a significant role in the selective reabsorption of peptide-bound amino acids as well as in the regulation of plasma concentrations for small peptides. This unique transport system also has significant pharmacological relevance in that it recognizes Beta3-lactam antibiotics (aminocephalosporins and aminopenicillins), anticancer compounds (bestatin), angiotensin-converting enzyme inhibitors (quinapril) and, as a result, is an important determinant of their pharmacokinetic profile, toxicity and therapeutic efficacy. However, systematic studies concerning the cellular basis of renal peptide transport are relatively few and there is almost no information on the heterogeneity of specific peptide transporters along the nephron. This proposal focuses on the characterization of oligopeptide transporters in mammalian kidney and, in particular, the study of PEPT1 and PEPT2, two isoforms in a novel and growing family of proton-coupled peptide transporters. Our specific aims are: Aim 1. to define the heterogeneity of peptide transport activity in different regions of mammalian kidney using brush border membrane vesicles and hybrid depletion studies. Aim 2. to determine the tissue distribution and tubular localization of PEPTI and PEPT2 in mammalian kidney. Aim 3. to characterize the substrate specificity of peptides and peptide- like drugs for specific oligopeptide transporters in mammalian kidney (i.e., PEPT1 and PEPT2) expressed in Xenopus laevis oocytes. The underlying hypothesis is that an understanding of peptide transporter heterogeneity (i.e., activity, distribution-localization, structure- function) will offer unique insights into the general principles of renal peptide-proton cotransport at a functional as well as molecular level. The knowledge gleaned from the proposed experiments will also have significant implications for the application, and perhaps design, of clinically important drugs used to treat infection, cancer, hypertension, congestive heart failure and potentially other disease states. Ultimately, these studies will pave the way for future proposals concerning the regulation of peptide transporters in kidney under physiological and pathological conditions.

专门的转运体，如肾肽转运系统，