1: Proximal-tubule molecular relay from early Protein diaphanous homolog 1 to late Rho-associated protein kinase 1 regulates kidney function in obesity-induced kidney damage.
Science of the Month - August 2022
Makiko Ida-Naitoh, Hirobumi Tokuyama, Koji Futatsugi, Marie Yasuda, Keika Adachi, Takeshi Kanda, Yoshiyuki Tanabe, Shu Wakino, Hiroshi Itoh
Obesity causes kidney damage, which has traditionally been reported to primarily involve glomerular injury. This study focused on changes in the proximal tubules in the very early stages of obesity, particularly tubular cell hypertrophy and kidney hypertrophy. In our laboratory, we have clarified the pathological significance of the small GTP-binding protein RhoA in cell hypertrophy using adipocytes. In this study, we found that tubular hypertrophy and kidney hypertrophy did not occur in obese mice in which RhoA in the proximal tubules was dominantly-negatively suppressed. We also revealed that in the early stages of obesity, when glomerular damage is not yet apparent, excessive activation of mDIA1, a downstream effector of RhoA, occurs in the proximal tubules, causing proximal tubular cell hypertrophy due to cell cycle arrest and cytoskeletal abnormalities. In the later stages, we found a shift from mDIA1 to excessive activation of ROCK, another downstream effector of RhoA, which contributes to kidney damage by causing inflammatory cytokine production due to tubular cell hypertrophy. The results of this study may provide valuable information for elucidating the pathophysiology of obesity-related kidney damage.
(Shu Wakino, Professor, Department of Nephrology, Tokushima University School of Medicine, Class of '69; Makiko Ida, Department of Internal Medicine, Hino Municipal Hospital)