Interaction between TGF-β and ACE2-Ang-(1-7)-Mas pathway in high glucose-cultured NRK-52E cells

Transforming growth factor-beta (TGF-beta) is pivotal in diabetic nephropathy (DN). Angiotensin converting enzyme-2 (ACE2) converts angiotensin II (Ang II) to angiotensin 1-7 (Ang-(1-7)), which binds to Mas. Proximal tubular ACE2 is decreased in DN. ACE2 deficiency exacerbates whereas ACE2 overexpression attenuates DN. Thus, we investigated the mechanism of high glucose-decreased ACE2 in terms of the interaction between TGF-beta and ACE2-Ang-(1-7)-Mas in NRK-52E cells. We found that high glucose increased TGF-beta. SB431542 attenuated high glucose-inhibited ACE2 and Mas and Ang-(1-7) conversion from Ang II while attenuating high glucose-induced fibronectin. TGF-beta 1 also decreased ACE2 and Mas and Ang-(1-7) conversion from Ang II. A779 attenuated Ang-(1-7)-decreased TGF-beta 1 and Ang-(1-7)-activated JAK2-STAT3. Moreover, A779, LY294002 and AG490 attenuated Ang-(1-7)-inhibited TGF-beta. The combination of Ang-(1-7) and Mas attenuated TGF-beta 1 (but not high glucose)-induced fibronectin. Thus, high glucose decreases ACE2 via TGF-beta R in NRK-52E cells. Additionally, there is a negative feedback function between TGF-beta and ACE2, and the combined inhibition of TGF-beta and activation of the ACE2-Ang-(1-7)-Mas may be useful for treating diabetic renal fibrosis. (C) 2012 Elsevier Ireland Ltd. All rights reserved.