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Viewed As a Sole Terbalance APA Deficiency

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Viewed As a Sole Terbalance APA Deficiency BASIC RESEARCH www.jasn.org Deficiency of the Angiotensinase Aminopeptidase A Increases Susceptibility to Glomerular Injury † † ‡ Juan Carlos Q. Velez,* Ehtesham Arif, Jessalyn Rodgers, Megan P. Hicks, † | † John M. Arthur,§ Deepak Nihalani, Evelyn T. Bruner, Milos N. Budisavljevic, † † Carl Atkinson,¶ Wayne R. Fitzgibbon, and Michael G. Janech *Department of Nephrology, Ochsner Clinic Foundation, New Orleans, Louisiana; †Division of Nephrology, Department of Medicine and Departments of |Pathology and ¶Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina; ‡Institute of Public and Preventative Health, Augusta University, Augusta, Georgia; and §Division of Nephrology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas ABSTRACT Aminopeptidase A (APA) is expressed in glomerular podocytes and tubular epithelia and metabolizes angiotensin II (AngII), a peptide known to promote glomerulosclerosis. In this study, we tested whether APA expression changes in response to progressive nephron loss or whether APA exerts a protective role against glomerular damage and during AngII-mediated hypertensive kidney injury. At advanced stages of FSGS, fawn-hooded hypertensive rat kidneys exhibited distinctly increased APA staining in areas of intact glomerular capillary loops. Moreover, BALB/c APA-knockout (KO) mice in- jected with a nephrotoxic serum showed persistent glomerular hyalinosis and albuminuria 96 hours after injection, whereas wild-type controls achieved virtually full recovery. We then tested the effect of 4-week infusion of AngII (400 ng/kg per minute) in APA-KO and wild-type mice. Although we observed no significant difference in achieved systolic BP, AngII-treated APA-KO mice developed a significant rise in albuminuria not observed in AngII-treated wild-type mice along with increased segmental and global sclerosis and/or collapse of juxtamedullary glomeruli, microcystic tubular dilation, and tubulointerstitial fibrosis. In parallel, AngII treatment significantly increased the kidney AngII content and attenuated the expression of podocyte nephrin in APA-KO mice but not in wild-type controls. These data show that deficiency of APA increases susceptibility to glomerular injury in BALB/c mice. The augmented AngII-mediated kidney injury observed in association with increased intrarenal AngII accumulation in the absence of APA suggests a protective metabolizing role of APA in AngII-mediated glomerular diseases. J Am Soc Nephrol 28: 2119–2132, 2017. doi: https://doi.org/10.1681/ASN.2016111166 Aminopeptidase A (APA; glutamyl aminopeptidase; whereas neprilysin (NEP) converts AngII into two EC 3.4.11.7) is a homodimeric membrane–bound tetrapeptides, Ang1–4andAng5–8.3–8 Although zinc metallopeptidase capable of hydrolyzing an- these peptidases are ubiquitously expressed through- giotensin (Ang) peptides. Through cleavage at the out the body, differences in their cellular localization amino terminus, APA initiates the metabolism of the octapeptide AngII by converting it into the Received November 2, 2016. Accepted January 4, 2017. heptapeptide AngIII, which is further metabolized Published online ahead of print. Publication date available at rapidly by aminopeptidase N (APN) into AngIV.1,2 www.jasn.org. Other peptidases are capable of metabolizing AngII Correspondence: Dr. Juan Carlos Q. Velez, 1514 Jefferson at the carboxy terminus to convert it into Ang1–7 Highway, 5th Floor, Clinic Tower, Ochsner Medical Center, New (e.g., angiotensin-converting enzyme 2 [ACE2], Orleans, LA 70121. Email: [email protected] prolyl endopeptidase, and prolyl carboxypeptidase), Copyright © 2017 by the American Society of Nephrology J Am Soc Nephrol 28: 2119–2132, 2017 ISSN : 1046-6673/2807-2119 2119 BASIC RESEARCH www.jasn.org experimental and human glomerular disease have revealed conflicting data: some report- ing an increase in APA expression and others reporting a decrease.23–26 Using a robust model of spontaneous FSGS, the fawn-hooded hypertensive (FHH) rat, we sought to explore whether an adaptive change in pattern of glomeru- lar APA expression is present during pro- gressive nephron loss. Subsequently, we tested whether APA deficiency could influ- ence the reversibility of damage acquired in an established mouse model of glomer- ular injury, the sheep anti-rat glomerular lysate antiserum (nephrotoxic serum – Figure 1. Pattern of glomerular APA expression changes during progressive glo- [NTS]) injection model.27 29 Next, be- merulosclerosis. Examination of glomerular APA expression in 60-week-old FHH rat cause of its inherent property as an AngII- kidneys by (A) immunohistochemistry. In comparison with normal age-matched Wistar degrading enzyme, we examined the role rat kidneys that revealed uniform glomerular APA staining, FHH rat glomeruli showed of APA in a well established mouse model a heterogeneous pattern of expression, with a mixture of globally sclerotic glomeruli of AngII-dependent hypertensive kidney showing virtually no APA expression, segmentally sclerotic glomeruli with enhanced injury, the chronic AngII infusion APA staining in the nonsclerotic segments, and fully preserved glomeruli with overall model.30–32 We hypothesized that glomer- increased APA staining. Examination of APA expression in glomerular extracts ular APA expression changes as part of an (pooled from three rats per lane) by (B) Western blotting showed progressive loss fi adaptive response to injury. Then, we hy- of total APA over time along with a parallel progressive increase in bronectin (FN). fi The upper band for APA represents a mature transmembrane domain, whereas the pothesized that de ciency of APA could lower band corresponds to an immature endoplasmic reticulum fraction. Examination result in exacerbated glomerular injury in of APA expression in (C) human kidneys of a transplant healthy donor and an indi- response to a noxious stimuli, such as the vidual with FSGS also revealed a similar distinct patter of APA expression. Scale bars, NTS. In addition, we hypothesized that, 200 mm. during systemic exposure to exogenous AngII, full deficiency of APA may lead to reduced AngII degradation, increased in- and tissue distribution may have implications in tissue concen- trarenal accumulation of AngII, and subsequent augmented tration of AngII in health and disease. renal parenchymal injury. Studies indicate that APA, APN, NEP, ACE2, and prolyl car- boxypeptidase are involved in AngII enzymatic processing in the kidney.1,9–12 However, intrarenal APA has the highest relative RESULTS tissue abundance and enzymatic activity compared with the other peptidases.13–15 Because APA is localized in glomerular Pattern of Adaptive Kidney APA Expression during podocytes,16,17 tubular epithelia,17 and medullary endothelial Progressive FSGS cells,16 it is critical for AngII metabolism in all kidney compart- Using the FHH rat model, we examined the pattern of glomer- ments. However, the notable localization of APA in podocytes is ular expression of APA during the course of the disease. In highlighted by studies showing that intravenous injection of comparison with normal age-matched Wistar rats, kidney APA mAb against APA in mice induces overt podocyte foot process expression changed at advanced stages (Figure 1A). Obsoles- effacement, glomerular granular IgG deposition, and albumin- cent glomeruli lost virtually all expression of APA. However, uria.18,19 Importantly, the kidneys possess the most robust en- coexisting surviving glomeruli exhibited prominent APA zymatic capacity to degrade AngII in the body, with up to 93% of staining. Additionally, intact areas within segmentally sclerotic AngII being degraded as it passes through the kidney compared glomeruli also showed prominent APA staining. Notwith- with 60% through systemic circulation and only 5% through standing the observed heterogeneity in glomerular APA ex- pulmonary circulation, and up to 60% of that intrarenal metab- pression, the total glomerular APA expression decreased over olism is mediated by APA.1 Despite those observations regarding time as shown by Western blotting of glomerular homoge- APA localization and function and the widely established notion nates. The upper band for APA represents a mature trans- that AngII promotes progressive glomerulosclerosis,20–22 the membrane domain protein post-Golgi processing, whereas role of APA-mediated AngII degradation in attenuating AngII- the lower band corresponds to an immature endoplasmic re- mediated kidney injury has not been elucidated. Furthermore, ticulum fraction.33 In contrast, glomerular fibronectin abun- studies examining the glomerular expression of APA in dance increased over time (Figure 1B). Furthermore, a kidney 2120 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 2119–2132, 2017 www.jasn.org BASIC RESEARCH Renal Characterization of APA- Knockout Mice Lack of expression of APA in kidneys of BALB/c APA-knockout (KO) mice was veri- fied by immunohistochemistry. Staining in BALB/cwild-typemice showedexpressionin podocytes and proximal tubules (Figure 3A). Immunofluorescence studies confirmed co- localization of APA and nephrin in wild-type mouse podocytes and complete absence of APA in APA-KO mice (Figure 3B). Images show APA localization at the body of the po- docyte as well as colocalization of APA and nephrin at the slit diaphragms, consistent with a previous report.18 In addition, func- tional deficiency of intrarenal APA was veri- fied in whole-kidney extracts
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