Functional expression of the renin-angiotensin system in human podocytes

被引:107
作者
Liebau, MC
Lang, D
Böhm, J
Endlich, N
Bek, MJ
Witherden, I
Mathieson, PW
Saleem, MA
Pavenstädt, H
Fischer, KG
机构
[1] Univ Hosp Freiburg, Dept Med, Div Nephrol & Gen Med, Freiburg, Germany
[2] Univ Hosp, Dept Med D, Div Gen Internal Med & Nephrol, Munster, Germany
[3] Univ Freiburg, Dept Pathol, D-7800 Freiburg, Germany
[4] Heidelberg Univ, Dept Anat & Cell Biol, Heidelberg, Germany
[5] Univ Bristol, Southmead Hosp, Childrens Renal Unit, Bristol, Avon, England
[6] Univ Bristol, Southmead Hosp, Acad Renal Unit, Bristol, Avon, England
基金
英国医学研究理事会;
关键词
cytosolic Ca2+; human; captopril; AT(1) receptor; AT(2) receptor; apoptosis; mechanical stress;
D O I
10.1152/ajprenal.00475.2004
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 AT1 and AT2 receptor was demonstrated both in differentiated human podocytes and in human kidney cortex. ANG II induced a concentration-dependent increase in cytosolic Ca2+ concentration via AT1 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.
引用
收藏
页码:F710 / F719
页数:10
相关论文
共 51 条
[31]   Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency [J].
Maschio, G ;
Alberti, D ;
Janin, G ;
Locatelli, F ;
Mann, JFE ;
Motolese, M ;
Ponticelli, C ;
Ritz, E ;
Zucchelli, P ;
Marai, P ;
Marcelli, D ;
Tentori, F ;
Andriani, M ;
Drago, G ;
Meneghel, G ;
Oldrizzi, L ;
Rugiu, C ;
Salvadeo, A ;
Villa, G ;
Picardi, L ;
Borghi, M ;
Moriggi, M ;
Vendramin, G ;
Fusaroli, M ;
Esposti, ED ;
Fabbri, A ;
Koch, KM ;
Frey, U ;
Schaeffer, J ;
Mann, J ;
Schweitzer, C ;
Zuccala, A ;
Gaggi, R ;
Stahl, R ;
Blaser, C ;
Rivolta, E ;
Buccianti, G ;
Gastaldi, L ;
Baratelli, M ;
Ducret, F ;
Pointet, P ;
Sterzel, R ;
Oberdorf, E ;
Pedrini, L ;
Faranna, P ;
Cairo, G ;
Ferrari, L ;
Albertazzi, A ;
Cappelli, P ;
Cantu, P .
NEW ENGLAND JOURNAL OF MEDICINE, 1996, 334 (15) :939-945
[32]  
Mifsud SA, 2001, DIABETOLOGIA, V44, P878
[33]   Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and Lisinopril microalbuminuria (CALM) study [J].
Mogensen, CE ;
Neldam, S ;
Tikkanen, I ;
Oren, S ;
Viskoper, R ;
Watts, RW ;
Cooper, ME .
BMJ-BRITISH MEDICAL JOURNAL, 2000, 321 (7274) :1440-1444
[34]  
Mundel P, 1997, J AM SOC NEPHROL, V8, P697
[35]   RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial (Retracted article. See vol. 374, pg. 1226, 2009) [J].
Nakao, N ;
Yoshimura, A ;
Morita, H ;
Takada, M ;
Kayano, T ;
Ideura, T .
LANCET, 2003, 361 (9352) :117-124
[36]   Regulation of intrarenal angiotensin II in hypertension [J].
Navar, LG ;
Harrison-Bernard, LM ;
Nishiyama, A ;
Kobori, H .
HYPERTENSION, 2002, 39 (02) :316-322
[37]   Chronic administration of nitric oxide reduces angiotensin II receptor type 1 expression and aldosterone synthesis in zona glomerulosa cells [J].
Nithipatikom, K ;
Holmes, BB ;
McCoy, MJ ;
Hillard, CJ ;
Campbell, WB .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2004, 287 (05) :E820-E827
[38]   ANTIDIURETIC-HORMONE ACTS VIA V1 RECEPTORS ON INTRACELLULAR CALCIUM IN THE ISOLATED PERFUSED RABBIT CORTICAL THICK ASCENDING LIMB [J].
NITSCHKE, R ;
FROBE, U ;
GREGER, R .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1991, 417 (06) :622-632
[39]   Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus [J].
Nitschke, R ;
Henger, A ;
Ricken, S ;
Gloy, J ;
Müller, V ;
Greger, R ;
Pavenstädt, H .
KIDNEY INTERNATIONAL, 2000, 57 (01) :41-49
[40]   Cell biology of the glomerular podocyte [J].
Pavenstädt, H ;
Kriz, W ;
Kretzler, M .
PHYSIOLOGICAL REVIEWS, 2003, 83 (01) :253-307