Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1flox/flox:Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD.
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Junya
J
Yamamoto
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: saorin@med.hokudai.ac.jp.
Saori
S
Nishio
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Fumihiko
F
Hattanda
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Daigo
D
Nakazawa
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Toru
T
Kimura
Liver Cancer Research Division, Kurume University, Kurume, Japan.
Michio
M
Sata
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Minoru
M
Makita
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Yasunobu
Y
Ishikawa
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tatsuya
T
Atsumi
D000597:Amino Acids, Branched-Chain / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D020935:MAP Kinase Signaling System; D051379:Mice; D016891:Polycystic Kidney, Autosomal Dominant / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000597:Amino Acids, Branched-Chain; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
ADPKD; BCAA; LAT-1; mTOR