Expression and Effect of Inhibition of Aminopeptidase-A during Nephrogenesis

Dijkman, Henry; Assmann, K.J.M.; Steenbergen, Eric J.; Wetzels, Jack F.M.

doi:10.1369/jhc.5a6815.2005

Cited by 8 publications

(11 citation statements)

References 19 publications

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“…No study has directly explored renin activity in podocytes. Our results suggest the existence of renin activity in podocytes, as evidenced by the formation of ANG I, ANG-(1-9), ANG II, and ANG-(1-7) after cells were incubated with ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). This conversion was inhibited by a renin inhibitor, demonstrating that the formation of angiotensin peptides from ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) is, in part, attributable to renin.…”

Section: Discussionmentioning

confidence: 52%

“…The conversion of ANG II to ANG III was inhibited by amastatin, an aminopeptidase A inhibitor. Aminopeptidase A is a 250-kDa transmembrane protein that cleaves ANG II to ANG III (40), and ANG III is subsequently converted to ANG IV by amniopeptidase N. The expression of aminopeptidase A in podocytes has been previously reported in developing kidneys (11). Highlighting the role of aminopeptidase A in the metabolism of ANG II and glomerular injury, Dijkman et al (12) found that mice injected with antibodies against aminopeptidase A developed proteinuria.…”

Section: Discussionmentioning

confidence: 97%

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Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes

Bland¹,

Arthur²,

Raymond³

et al. 2007

American Journal of Physiology-Renal Physiology

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Intraglomerular ANG II has been linked to glomerular injury. However, little is known about the contribution of podocytes (POD) to intraglomerular ANG II homeostasis. The aim of the present study was to examine the processing of angiotensin substrates by cultured POD. Our approach was to use matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for peptide determination from conditioned cell media and customized AQUA peptides for quantification. Immortalized mouse POD were incubated with 1-2 microM ANG I, ANG II, or the renin substrate ANG-(1-14) for different time intervals and coincubated in parallel with various inhibitors. Human mesangial cells (MES) were used as controls. POD incubated with 1 microM ANG I primarily formed ANG-(1-9) and 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 inhibitor. Modest angiotensin-converting enzyme (ACE) activity was also detected in POD, although only after cells were incubated with 2 microM ANG I. In addition, we observed that POD degraded ANG II into ANG III and ANG-(1-7). An aminopeptidase A inhibitor inhibited ANG III formation, and an ACE2 inhibitor led to ANG II accumulation. Furthermore, we found that POD converted ANG-(1-14) to 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 characterized by neprilysin, aminopeptidase A, ACE2, and renin activities, which 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 maintenance of intraglomerular renin-angiotensin system balance.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 97%

Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes

Bland¹,

Arthur²,

Raymond³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…Faint expression has also been observed in the juxtaglomerular cells, endothelial cells of the peritubular capillaries and in the pars media of the arteries (Assmann, et al, 1992;Dijkman, et al, 2006;Mentzel, et al, 1996b).…”

Section: Introductionmentioning

confidence: 94%

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

Tonna

Dandapani

Uscinski

et al. 2008

Gene

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The aminopeptidase A (APA) ectopeptidase is an integral membrane-bound zinc metalloprotease that cleaves aspartic and glutamic acidic residues from the N-terminus of a number of protein substrates that includes angiotensin II. Angiotensin II, the most vasoactive component of the reninangiotensin-aldosterone (RAAS) pathway, can contribute to renal disease by causing an increase in arterial blood pressure leading to glomerular injury and fibrosis. APA is expressed in many organs, including the kidney where it localizes mainly to the podocyte cell membrane and brush borders of the proximal tubule cells. Antibodies directed to the APA peptide can induce an acute massive albuminuria in wild type BALB/c mice after intravenous injection.We examined whether variants in the APA encoding gene (ENPEP) are more frequent in individuals with the proteinuric disease focal and segmental glomerulosclerosis (FSGS) compared to control individuals. The ENPEP coding sequence was resequenced in 188 FSGS patients and 48 controls. Genetic variants were further genotyped in 181 individuals without any known kidney disease. We then examined the effect of the non-synonymous coding variants identified on their cell surface APA activity after transfection in COS-1 cells.Several of these ENPEP variants lead to reproducibly altered APA activity. However, we did not see a clear correlation between the presence of a functional ENPEP variant and FSGS. However, the existence of these variants with marked effect on APA activity suggests that both rare and common variation in ENPEP may contribute to the development of renal and hypertensive disorders and warrants further study.

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“…Glutamyl aminopeptidase is a small membrane bound metalloprotease that cleaves N-terminal aspartyl and glutamyl residues from peptides (Dijkman et al, 2006). Its best-known target is Angiotensin II (Ang II) a component of the angiotensin-renin system (RAS) (Cogolludo et al, 2005; Reaux et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Its best-known target is Angiotensin II (Ang II) a component of the angiotensin-renin system (RAS) (Cogolludo et al, 2005; Reaux et al, 2001). The RAS system plays a role in the regulation of blood pressure and is also important for the development of the mammalian kidney (Dijkman et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

Transgenic labeling of the zebrafish pronephric duct and tubules using a promoter from the enpep gene

Seiler

Pack

2011

Gene Expression Patterns

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In recent years the zebrafish has become a popular model system to study organ development and disease. To facilitate these studies, genetic tools are required which allow to modify and manipulate gene expression in organs of interest. Here we describe a zebrafish 2.3kb glutamyl aminopeptidase (enpep) promoter fragment, and show that it can drive gene expression specifically in the kidney during early and late development. We established a stable transgenic line using this promoter fragment that has specific GFP expression in pronephric ducts and tubules starting at 20 hours post-fertilization.

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Expression and Effect of Inhibition of Aminopeptidase-A during Nephrogenesis

Cited by 8 publications

References 19 publications

Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes

Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

Transgenic labeling of the zebrafish pronephric duct and tubules using a promoter from the enpep gene

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