Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis

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.

doi:10.1152/ajprenal.00025.2018

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

Journal Article · 30 November 2018 · American Journal of Physiology-Renal Physiology

DOI: https://doi.org/10.1152/ajprenal.00025.2018 · OSTI ID:1502039

Trott, Josephine F. ^[1]; Hwang, Vicki J. ^[1]; Ishimaru, Tatsuto ^[1]; Chmiel, Kenneth J. ^[1]; Zhou, Julie X. ^[2]; Shim, Kyuhwan ^[3]; Stewart, Benjamin J. ^[4]; Mahjoub, Moe R. ^[5]; Jen, Kuang-Yu ^[6]; Barupal, Dinesh K. ^[7]; Li, Xiaogang ^[2]; Weiss, Robert H. ^[8]

Univ. of California, Davis, CA (United States). Division of Nephrology, Dept. of Internal Medicine
Univ. of Kansas, Lawrence, KS (United States). Medical Center, Kidney Inst., Dept. of Internal Medicine
Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Washington Univ., St. Louis, MO (United States). Division of Nephrology, Dept. of Medicine
Univ. of California, Davis, CA (United States). Dept. of Pathology
Univ. of California, Davis, CA (United States). West Coast Metabolomics Center
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

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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1502039

Report Number(s):: LLNL-JRNL--734198; 886144

Journal Information:: American Journal of Physiology-Renal Physiology, Journal Name: American Journal of Physiology-Renal Physiology Journal Issue: 6 Vol. 315; ISSN 1931-857X

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
arginine
cystogenesis
metabolic reprogramming

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

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