Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach

Abstract

Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor-alpha (TGF-alpha) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF-alpha or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-alpha and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Whereas most angiotensin-II actions are profibrotic, rare antifibrotic actions, for example of macrophage angiotensin-type 1 receptors, have been documented (226). TGF-a and its sheddase, TACE (also known as ADAM17) are other downstream mediators of the intrarenal profibrotic and injurious effects of angiotensin-II (227,228). Clinically, patient and allograft survival improved in individuals treated with an ACE-I or ARB (229) but this was not confirmed in large registry analyses (230).…”

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

“…Dietary phosphate restriction can significantly lower FGF-23 levels [53][54][55] and could be more effective if started before serum phosphate levels increase. Vitamin D receptor agonists may effectively inhibit both the TGF-␣-converting enzyme/TGF␣/EGF receptor pathway and the RAAS in the parathyroid and kidney 90,91 and reduce vascular calcification, podocyte damage, 63,[92][93][94] and proteinuria through blockade of Wnt/␤-catenin signaling. 95 Vitamin D receptor agonists also may upregulate klotho 96 and exert an antiinflammatory action through the reduction of nuclear factor B.…”

La fibrose tubulo-interstitielle rénale

“…Le FGF-2, quant à lui, stimule la TEM et la prolifération des fibroblastes ( Figure 3) [15] et son expression est augmentée dans des biopsies rénales de patients atteints de différentes néphropathies associées à la fibrose. Enfin, la stimulation de l'EGF-R par l'EGF potentialise l'effet du TGF- sur la TEM et son blocage in vivo diminue le dévelop-pement de la FTI dans différents modèles animaux de néphropathies ( Figure 3) [16,42]. À l'inverse, il existe des inhibiteurs endogènes de la fibrose et c'est la balance entre les facteurs pro-et antifibrosants qui détermine le devenir et la progression de Acide lysophosphatidique (LPA) Parmi tous les acteurs moléculaires impliqués dans la fibrose rénale, le LPA est un peu singulier.…”