Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway.
Glomerulosclerosis, interstitial fibrosis, and tubular atrophy occur with end-stage kidney failure, irrespective of the primary etiology. The transforming growth factor-beta (TGF-beta) is a key factor in these alterations either directly, by stimulating synthesis of extracellular matrix components and reducing collagenase production, or indirectly through other profibrogenic factors such as connective tissue growth factor (CTGF). TGF-beta is important for the proliferation of intrarenal fibroblasts and the epithelial-mesenchymal transition through which tubular cells become fibroblasts. Although several factors induce TGF-beta expression in the kidney, one very interesting aspect is the link between the renin-angiotensin-aldosterone (Aldo) system (RAAS) and TGF-beta. Angiotensin II (ANG II) stimulates TGF-beta expression in the kidney by various mechanisms and upregulates receptors for TGF-beta. ANG II can directly phosphorylate Smads without inducing TGF-beta. Recent data provide compelling evidence that other components of the RAAS including ANG III, renin, and Aldo also activate the TGF-beta system. As direct modulation of the TGF-beta system is not yet feasible in humans, angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT1)-receptor blockers are currently the most potential drugs to interfere with this ANG II-mediated TGF-beta expression. This review highlights some current aspects of the interaction between the RAAS and the TGF-beta axis.
Wolf
G
G
Klinik für Innere Medizin III, Klinikum der Friedrich-Schiller-Universität, Jena, Germany. Gunter.Wolf@med.uni-jena.de
D000804:Angiotensin II / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000473:pathology / Q000503:physiopathology*; D012084:Renin-Angiotensin System / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016212:Transforming Growth Factor beta; D000804:Angiotensin II