Biomedicine & Pharmacotherapy (Feb 2024)

Targeting ROCK1 in diabetic kidney disease: Unraveling mesangial fibrosis mechanisms and introducing myricetin as a novel antagonist

  • Ningning Yuan,
  • Jianxin Diao,
  • Jiamei Dong,
  • Yangtian Yan,
  • Yuchi Chen,
  • Shihua Yan,
  • Changshun Liu,
  • Zhuoen He,
  • Jinyue He,
  • Chi Zhang,
  • Hao Wang,
  • Mingqing Wang,
  • Fei He,
  • Wei Xiao

Journal volume & issue
Vol. 171
p. 116208

Abstract

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Diabetic kidney disease (DKD) stands as a pressing health challenge, with mesangial cell fibrosis identified as a pivotal hallmark leading to glomerular sclerosis. Gaining a deeper grasp on the molecular dynamics behind this can potentially introduce groundbreaking therapeutic avenues. Recent revelations from studies on ROCK1-deficient mice, which displayed resilience against high-fat diet (HFD)-induced glomerulosclerosis and mitochondrial fragmentation, spurred our hypothesis regarding ROCK1's potential role in mesangial cell fibrosis. Subsequent rigorous experiments corroborated our theory, highlighting the critical role of ROCK1 in orchestrating mesangial cell proliferation and fibrosis, especially in high-glucose settings. Mechanistically, ROCK1 inhibition led to a notable hindrance in the high-glucose-triggered MAPK signaling pathway, particularly emphasizing the ROCK1/ERK/P38 axis. To translate this understanding into potential therapeutic interventions, we embarked on a comprehensive drug screening journey. Leveraging molecular modeling techniques, Myricetin surfaced as an efficacious inhibitor of ROCK1. Dose-dependent in vitro assays substantiated Myricetin's prowess in curtailing mesangial cell proliferation and fibrosis via ROCK1/ERK/P38 pathway. In vivo verifications paralleled these findings, with Myricetin treatment resulting in significant renal function enhancements and diminished DKD pathological markers, all pivoted around the ROCK1/ERK/P38 nexus. These findings not only deepen our comprehension of DKD molecular underpinnings but also elevate ROCK1 to the pedestal of a promising therapeutic beacon. Concurrently, Myricetin is spotlighted as a potent natural contender, heralding a new era in DKD therapeutic design.

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