Interplay Between Growth Factor Receptors, Small GTPases, and Mechanical Stress in the Maintenance of Kidney Glomerular Homeostasis

Following injury, the damaged organ undergoes a repair process that results in the replacement of the injured tissue, with no lasting evidence of damage. A physiological process that occurs during tissue repair is fibroplasia, characterized by the replacement of normal parenchymal tissue with extracellular matrix (ECM) components. In normal conditions, the synthesis and degradation of ECM components are finely regulated by many different factors, including matrix and growth factor receptors, reactive oxygen species, hormones, and cytokines. When fibroplasia goes unchecked, the final product is unwanted and irreversible tissue scarring, with consequent organ damage, organ failure, and in the certain cases death. In the kidneys, glomerulosclerosis is a general term for scarring of the glomerulus, the filtering unit of the kidney. Glomerulosclerosis is an irreversible event and as ECM accumulates the diseased kidney progresses to end stage renal disease. Many factors such as matrix and growth factor receptors, small GTPases, and mechanical stress play a role in the development of glomerulosclerosis. The generation of animal models overexpressing and/or lacking key factors thought to regulate glomerular matrix homeostasis has improved our understanding of molecular mechanisms and pathways controlling matrix remodeling in health and disease. In this chapter, we outline the molecular mechanisms whereby growth factor receptors, small GTPases, and mechanical stress contribute to glomerulosclerosis and highlight how targeting these factors might be beneficial in the setting of glomerular injury.