Functional expression of the renin-angiotensin system in human podocytes.
Experimental and clinical studies impressively demonstrate that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) significantly reduce proteinuria and retard progression of glomerular disease. The underlying intraglomerular mechanisms are not yet fully elucidated. As podocyte injury constitutes a critical step in the pathogenesis of glomerular proteinuria, beneficial effects of ACEI and ARB may partially result from interference with a local renin-angiotensin system (RAS) in podocytes. The knowledge of expression and function of a local RAS in podocytes is limited. In this study, we demonstrate functional expression of key components of the RAS in differentiated human podocytes: podocytes express mRNA for angiotensinogen, renin, ACE type 1, and the AT(1) and AT(2) angiotensin receptor subtypes. In Western blot experiments and immunostainings, expression of the AT(1) and AT(2) receptor was demonstrated both in differentiated human podocytes and in human kidney cortex. ANG II induced a concentration-dependent increase in cytosolic Ca(2+) concentration via AT(1) receptors in differentiated human podocytes, whereas it did not increase cAMP. Furthermore, ANG II secretion was detected, which was blocked by neither the ACEI captopril nor the renin inhibitor remikiren nor the chymase inhibitor chymostatin. ANG II secretion of podocytes was not increased by mechanical stress. Finally, ANG II was found to increase staurosporine-induced apoptosis in podocytes. We speculate that ACEI and ARB exert their beneficial effects, in part, by interfering with a local RAS in podocytes. Further experiments are required to identify the underlying molecular mechanism(s) of podocyte protection.
Liebau
Max C
MC
Department of Medicine, Division of Nephrology and General Medicine, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
Lang
D
D
Böhm
J
J
Endlich
N
N
Bek
Martin J
MJ
Witherden
Ian
I
Mathieson
Peter W
PW
Saleem
Moin A
MA
Pavenstädt
Hermann
H
Fischer
Karl-Georg
KG
D000808:Angiotensinogen / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D005786:Gene Expression Regulation; D006801:Humans; D050199:Podocytes / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*
D017931:DNA Primers; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D012083:Renin