skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis

Abstract

Research into metabolic reprogramming in cancer has become commonplace, yet this area of research has only recently come of age in nephrology. In light of the parallels between cancer and autosomal dominant polycystic kidney disease (ADPKD), the latter is currently being studied as a metabolic disease. In clear cell renal cell carcinoma (RCC), which is now considered a metabolic disease, we and others have shown derangements in the enzyme arginosuccinate synthase 1 (ASS1), resulting in RCC cells becoming auxotrophic for arginine and leading to a new therapeutic paradigm involving reducing extracellular arginine. Based on our earlier finding that glutamine pathways are reprogrammed in ARPKD, and given the connection between arginine and glutamine synthetic pathways via citrulline, we investigated the possibility of arginine reprogramming in ADPKD. Here, we now show that, in a remarkable parallel to RCC, ASS1 expression is reduced in murine and human ADPKD, and arginine depletion results in a dose-dependent compensatory increase in ASS1 levels as well as decreased cystogenesis in vitro and ex vivo with minimal toxicity to normal cells. Nontargeted metabolomics analysis of mouse kidney cell lines grown in arginine-deficient versus arginine-replete media suggests arginine-dependent alterations in the glutamine and proline pathways. Thus, depletion of thismore » conditionally essential amino acid by dietary or pharmacological means, such as with arginine-degrading enzymes, may be a novel treatment for this disease.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [4];  [5];  [6];  [7];  [2];  [8]
  1. Univ. of California, Davis, CA (United States). Division of Nephrology, Dept. of Internal Medicine
  2. Univ. of Kansas, Lawrence, KS (United States). Medical Center, Kidney Inst., Dept. of Internal Medicine
  3. Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri
  4. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  5. Washington Univ., St. Louis, MO (United States). Division of Nephrology, Dept. of Medicine
  6. Univ. of California, Davis, CA (United States). Dept. of Pathology
  7. Univ. of California, Davis, CA (United States). West Coast Metabolomics Center
  8. Univ. of California, Davis, CA (United States). Division of Nephrology, Dept. of Internal Medicine; Univ. of California, Davis, CA (United States). Dept. of Pathology; VA Northern California Health Care System, Sacramento, CA (United States). Medical Service
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1502039
Report Number(s):
LLNL-JRNL-734198
Journal ID: ISSN 1931-857X; 886144
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
American Journal of Physiology-Renal Physiology
Additional Journal Information:
Journal Volume: 315; Journal Issue: 6; Journal ID: ISSN 1931-857X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; arginine; cystogenesis; metabolic reprogramming

Citation Formats

Trott, Josephine F., Hwang, Vicki J., Ishimaru, Tatsuto, Chmiel, Kenneth J., Zhou, Julie X., Shim, Kyuhwan, Stewart, Benjamin J., Mahjoub, Moe R., Jen, Kuang-Yu, Barupal, Dinesh K., Li, Xiaogang, and Weiss, Robert H.. Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis. United States: N. p., 2018. Web. doi:10.1152/ajprenal.00025.2018.
Trott, Josephine F., Hwang, Vicki J., Ishimaru, Tatsuto, Chmiel, Kenneth J., Zhou, Julie X., Shim, Kyuhwan, Stewart, Benjamin J., Mahjoub, Moe R., Jen, Kuang-Yu, Barupal, Dinesh K., Li, Xiaogang, & Weiss, Robert H.. Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis. United States. doi:10.1152/ajprenal.00025.2018.
Trott, Josephine F., Hwang, Vicki J., Ishimaru, Tatsuto, Chmiel, Kenneth J., Zhou, Julie X., Shim, Kyuhwan, Stewart, Benjamin J., Mahjoub, Moe R., Jen, Kuang-Yu, Barupal, Dinesh K., Li, Xiaogang, and Weiss, Robert H.. Sat . "Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis". United States. doi:10.1152/ajprenal.00025.2018.
@article{osti_1502039,
title = {Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis},
author = {Trott, Josephine F. and Hwang, Vicki J. and Ishimaru, Tatsuto and Chmiel, Kenneth J. and Zhou, Julie X. and Shim, Kyuhwan and Stewart, Benjamin J. and Mahjoub, Moe R. and Jen, Kuang-Yu and Barupal, Dinesh K. and Li, Xiaogang and Weiss, Robert H.},
abstractNote = {Research into metabolic reprogramming in cancer has become commonplace, yet this area of research has only recently come of age in nephrology. In light of the parallels between cancer and autosomal dominant polycystic kidney disease (ADPKD), the latter is currently being studied as a metabolic disease. In clear cell renal cell carcinoma (RCC), which is now considered a metabolic disease, we and others have shown derangements in the enzyme arginosuccinate synthase 1 (ASS1), resulting in RCC cells becoming auxotrophic for arginine and leading to a new therapeutic paradigm involving reducing extracellular arginine. Based on our earlier finding that glutamine pathways are reprogrammed in ARPKD, and given the connection between arginine and glutamine synthetic pathways via citrulline, we investigated the possibility of arginine reprogramming in ADPKD. Here, we now show that, in a remarkable parallel to RCC, ASS1 expression is reduced in murine and human ADPKD, and arginine depletion results in a dose-dependent compensatory increase in ASS1 levels as well as decreased cystogenesis in vitro and ex vivo with minimal toxicity to normal cells. Nontargeted metabolomics analysis of mouse kidney cell lines grown in arginine-deficient versus arginine-replete media suggests arginine-dependent alterations in the glutamine and proline pathways. Thus, depletion of this conditionally essential amino acid by dietary or pharmacological means, such as with arginine-degrading enzymes, may be a novel treatment for this disease.},
doi = {10.1152/ajprenal.00025.2018},
journal = {American Journal of Physiology-Renal Physiology},
issn = {1931-857X},
number = 6,
volume = 315,
place = {United States},
year = {2018},
month = {12}
}

Journal Article:
Free Publicly Available Full Text
This content will become publicly available on December 1, 2019
Publisher's Version of Record

Save / Share: