Angiotensin-[1–7] attenuates kidney injury in experimental Alport syndrome

Angiotensin-[1–7] (Ang-[1–7]) antagonize the actions of the renin-angiotensin-system via the Mas receptor and thereby exert renoprotective effects. Murine recombinant angiotensin-converting enzyme (ACE)2 was reported to show renoprotective effects in an experimental Alport syndrome model; however, the protective effect of direct administration of Ang-[1–7] is unknown. Here, we used Col4a3(−/−) mice as a model of Alport syndrome, which were treated with saline or Ang- [1–7]; saline-treated wild-type mice were used as a control group. The mice were continuously infused with saline or Ang-[1–7] (25 μg/kg/h) using osmotic mini-pumps. Col4a3(−/−) mice showed increased α-smooth muscle actin (SMA), collagen, and fibronectin expression levels, which were attenuated by Ang-[1–7] treatment. Moreover, Ang-[1–7] alleviated activation of transforming growth factor-β/Smad signaling, and attenuated the protein expression of ED-1 and heme oxygenase-1, indicating reduction of renal inflammation. Ang-[1–7] treatment further reduced the expression levels of inflammatory cytokines and adhesion molecules and attenuated apoptosis in human kidney cells. Finally, Ang-[1–7] downregulated TNF-α converting enzyme and upregulated ACE2 expression. Thus, treatment with Ang-[1–7] altered the ACE2-Ang-[1–7]-Mas receptor axis in the kidneys of Col4a3(−/−) mice to attenuate the nephropathy progression of Alport syndrome.