Rac1 promotes proximal tubule kidney repair by coupling the actin cytoskeleton to mitochondrial function
Abstract
The kidney proximal tubule (PT) is a specialized polarized epithelium that functions as a high capacity resorptive machine. PT cells are exquisitely sensitive to ischemia due to their high metabolic rate. The small GTPase Rac1 regulates epithelial function by promoting polarity through its effects on the actin cytoskeleton. We show that Rac1, in the setting of the recovery of the PT from ischemic injury, plays a critical role in reconstituting cellular bioenergetics by promoting actin cytoskeleton formation around damaged mitochondria. This mechanism removes damaged mitochondria through mitophagy and preserves PT metabolic capacity and reabsorption function. Loss of Rac1 causes intracellular lipid accumulation, energy depletion, and PT cell atrophy. Thus, Rac1 promotes the repair of PT cells by enhancing mitochondrial bioenergetics, rather than by regulating cell polarity via a mechanism that links the actin cytoskeleton to metabolic demands and cell morphology.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Olga M. Viquez
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Meiling Melzer
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Shensen Li
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Matthew Tantengco
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Xinyu Dong
Key Laboratory of Photochemistry
Eric Sha
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Jeffery Huang
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Evan S. Krystofiak
Department of Cell and Developmental Biology, Vanderbilt University
Rachel C. Hart
Department of Cell and Developmental Biology, Vanderbilt University
Wentian Luo
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Christian Warren
Research and Medical Services, United States Department of Veterans Affairs, Tennessee Valley Healthcare System
Al-Borhan Bayazid
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Richard Zhang
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Ryoichi Bessho
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Volker H. Haase
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Cord Brakebusch
Takanari Inoue
Department of Cell Biology, Johns Hopkins University School of Medicine
Craig Brooks
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Matthew H. Wilson
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Andrew S. Terker
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Juan P. Arroyo
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Ambra Pozzi
Roy Zent
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center
Fabian Bock
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center