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1 Research, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, United States; Medicine/Nephrology, Medical University of South Carolina, Charleston, South Carolina, United States
2 Medicine/Nephrology, Medical University of South Carolina, Charleston, South Carolina, United States
* To whom correspondence should be addressed. E-mail: velezj{at}musc.edu.
Intraglomerular angiotensin-II (ANG-II) has been linked to glomerular injury. However, little is known whether podocytes (POD) contribute to intraglomerular ANG-II homeostasis. The aim of the study was to examine the processing of angiotensin substrates by cultured POD. Our approach was to use MALDI-TOF mass spectrometry for peptide determination from conditioned cell media, using customized AQUA-peptides for quantification. Immortalized mouse POD were incubated with 1-2mcM of angiotensin-I (ANG-I), ANG-II or the renin substrate angiotensin-(1-14) (ANG-1-14), for different time intervals, and co-incubated in parallel with various inhibitors. Human mesangial cells (MES) were used as controls. We found that POD incubated with 1mcM of ANG-I primarily formed angiotensin-(1-9) (ANG-1-9) and angiotensin-(1-7) (ANG-1-7). In contrast, MES incubated with ANG-I primarily generated ANG-II. In POD, ANG-1-7 was the predominant product and its formation was inhibited by a neprilysin (NEP) inhibitor. Modest ACE activity was also detected in POD, although only after cells were incubated with 2mcM of ANG-I. In addition, we observed that POD degraded ANG-II into angiotensin-III (ANG-III) and ANG-1-7. While an aminopeptidase-A (APA) inhibitor inhibited the formation of ANG-III, an ACE2 inhibitor led to ANG-II accumulation. Furthermore, we found that POD converted ANG-1-14 into ANG-I and ANG-1-7. This conversion was inhibited by a renin inhibitor. These findings demonstrate that POD express a functional intrinsic renin-angiotensin-system (RAS) characterized by NEP, APA, ACE2 and renin activities that predominantly lead to ANG-1-7 and ANG-1-9 formation, as well as ANG-II degradation. These findings may reflect a specific role of POD in maintaining intraglomerular RAS balance.
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