TGF-β/BMP proteins as therapeutic targets in renal fibrosis. Where have we arrived after 25 years of trials and tribulations?
The understanding of renal fibrosis in chronic kidney disease (CKD) remains as a challenge. More than 10% of the population of developed countries suffer from CKD. Proliferation and activation of myofibroblasts and accumulation of extracellular matrix proteins are the main features of kidney fibrosis, a process in which a large number of cytokines are involved. Targeting cytokines responsible for kidney fibrosis development might be an important strategy to face the problem of CKD. The increasing knowledge of the signaling pathway network of the transforming growth factor beta (TGF-β) superfamily members, such as the profibrotic cytokine TGF-β1 or the bone morphogenetic proteins (BMPs), and their involvement in the regulation of kidney fibrosis, has stimulated numerous research teams to look for potential strategies to inhibit profibrotic cytokines or to enhance the anti-fibrotic actions of other cytokines. The consequence of all these studies is a better understanding of all these canonical (Smad-mediated) and non-canonical signaling pathways. In addition, the different receptors involved for signaling of each cytokine, the different combinations of type I-type II receptors, and the presence and function of co-receptors that can influence the biological response have been also described. However, are these studies leading to suitable strategies to block the appearance and progression of kidney fibrosis? In this review, we offer a critical perspective analyzing the achievements using the most important strategies developed up till now: TGF-β antibodies, chemical inhibitors of TGF-β receptors, miRNAs and signaling pathways and BMP agonists with a potential role as therapeutic molecules against kidney fibrosis.
Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
José M
JM
Muñoz-Félix
Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
María
M
González-Núñez
Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Hospital Universitario de Salamanca, Salamanca, Spain.
Carlos
C
Martínez-Salgado
Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. Electronic address: jmlnovoa@usal.es.
José M
JM
López-Novoa
D019485:Bone Morphogenetic Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000473:pathology*; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000473:pathology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1
Bone morphogenetic proteins; Inhibitors; Kidney fibrosis; Smad proteins; TGF-β1; micro-RNAs