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¹ Department of Nephrology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain ² Division of Nephrology & Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA

	Abstract

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
Angiotensin-converting enzyme (ACE) 2 is a homologue of ACE with enzymatic activity that seems to counterbalance the angiotensin II-promoting effect of ACE. While ACE promotes angiotensin (Ang) II formation from Ang I, ACE2 degrades Ang II and Ang I. In this review, we discuss recent studies that have delineated the localization of ACE2 within the kidney, an organ that highly expresses this enzyme. In models of diabetic kidney, pharmacological ACE2 inhibition is associated with albuminuria and worsening of glomerular injury. Similarly, genetic ablation of ACE2 causes glomerular lesions in male mice and worsens the renal lesions seen in diabetic Akita mice. Taken together, these findings suggest that a decrease in ACE2 may be involved in diabetic kidney disease, possibly by disrupting the metabolism of angiotensin peptides in such a way that angiotensin II degradation within the glomerulus may be diminished.

(Received 12 November 2007; accepted after revision 17 January 2008; first published online 25 January 2008)
Corresponding author D. Batlle: Division of Nephrology & Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, 320 E Superior, Chicago, IL 60611, USA. Email: d-batlle{at}northwestern.edu

	Introduction

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that catalyses angiotensin (Ang) II formation from Ang I (Turner & Hooper, 2002; Acharya et al. 2003). Recently, three mammalian homologues of ACE, namely ACE2, collectrin and ACE3, have been described (Donoghue et al. 2000; Zhang et al. 2001; Crackower et al. 2002; Rella et al. 2007). Angiotensin-converting enzyme 2 is the only known homologue of ACE with enzymatic activity; it is abundantly expressed in the kidney and may counterbalance ACE activity by promoting Ang II degradation to the vasodilator peptide Ang(1–7) (Brosnihan et al. 1996; Santos et al. 2000). Angiotensin(1–7) acts on the Mas receptor and is increasingly recognized as a biologically active peptide (Carvalho et al. 2007; Sampaio et al. 2007; Santos et al. 2007). In addition, ACE2 also catalyses conversion of Ang I to the inactive peptide Ang(1–9) (Donoghue et al. 2000; Crackower et al. 2002).

The Ace2 gene maps to the human X chromosome and encodes an 805-amino-acid membrane-bound glycoprotein (Donoghue et al. 2000; Tipnis et al. 2000). The ACE2 enzyme exhibits 42% sequence identity and 61% sequence similarity to ACE. Moreover, ACE2 contains a single zinc-binding domain HEXXH, which is homologous to the active sites of ACE; however, it is not inhibited by ACE inhibitors (Donoghue et al. 2000; Tipnis et al. 2000). Initially, ACE2 was thought to be restricted to the kidney, heart and testes (Donoghue et al. 2000; Tipnis et al. 2000) Subsequently, ACE2 was found in other organs, such as lungs, liver, central nervous system and placenta (Hamming et al. 2004; Imai et al. 2005; Paizis et al. 2005; Doobay et al. 2007; Valdes et al. 2006; Xie et al. 2006). In this review we summarize recent studies that have delineated the localization of ACE2 within the kidney and have suggested a possible involvement in diabetic nephropathy (Tikellis et al. 2003; Ye et al. 2004; Wysocki et al. 2006,; Ye et al. 2006; Wong et al. 2007). These studies suggest that ACE2 is emerging as a potential target for the development of strategies for the treatment of diabetic nephropathy. Our review is limited to ACE2 and the kidney since the importance of ACE2 for cardiovascular disease and other pathologies is being discussed elsewhere in this issue of Experimental Physiology.

	Localization of ACE2 in the kidney

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
Under physiological conditions, ACE2 expression varies widely within tissues and species (Gembardt et al. 2005). In mouse kidney, ACE2 is highly expressed (Ye et al. 2004, 2006). Wysocki and co-workers, using a fluorogenic assay, found that the activity of ACE2 was higher in mouse kidney cortex than in mouse heart tissue (Wysocki et al. 2006,). In mouse kidney, ACE and ACE2 have been co-localized by confocal microscopy in the brush border of proximal tubules (Ye et al. 2006; Fig. 1). In glomeruli, however, both enzymes are localized in distinct structures (Ye et al. 2006; Fig. 1). Within the glomerulus, ACE2 is mainly present in glomerular epithelial cells (Fig. 2) and, to a lesser extent, in glomerular mesangial cells (Ye et al. 2006). Glomerular ACE, by contrast, is localized only in endothelial cells (Fig. 3). The presence of ACE2 in glomerular epithelial cells was further delineated using immunogold studies (Ye et al. 2006; Fig. 4). In cultured immortalized podocytes, we have also detected the presence of ACE2 at the protein level, whereas ACE was not detectable at the protein level (Wysocki et al. 2006a).

View larger version (107K): [in this window] [in a new window]   Figure 1.  Immunofluorescence staining of ACE and ACE2 in proximal tubule and glomerulus Upper panels show immunofluorescence staining of ACE (green; left) and ACE2 (red; middle) in proximal tubules. Merging of both images (yellow; right) shows co-localization of ACE and ACE2 at the apical site of proximal tubules. Lower panels show immunofluorescence staining of ACE (green; left) and ACE2 (red; middle) in a glomerulus from mouse kidney. Merging of both images shows essentially no co-localization of ACE and ACE2 in the glomerulus (right). Reproduced from Ye et al. (2006), with permission.

View larger version (91K): [in this window] [in a new window]   Figure 2.  Immunofluorescence staining of ACE, ACE2 and nephrin in the glomerulus Triple immunofluorescence staining of ACE (green; A), ACE2 (red; D) and the podocyte slit diaphragm marker nephrin (blue; B and E). Merged images show that ACE does not co-localize with nephrin (C), whereas ACE2 clearly co-localizes with nephrin (pink, arrows; F). Reproduced from Ye et al. (2006), with permission.

View larger version (109K): [in this window] [in a new window]   Figure 3.  Immunofluorescence staining of ACE, ACE2 and PECAM-1 in the glomerulus Triple immunofluorescence staining of ACE (green; A), ACE2 (red; D) and the endothelial cell marker platelet-endothelial cell adhesion molecule (PECAM-1; blue; B and E). Merged images show that ACE strongly co-localizes with PECAM-1 (light blue, arrows; C), whereas ACE2 does not co-localize with PECAM-1 (F). Adapted from Ye et al. (2006).

View larger version (74K): [in this window] [in a new window]   Figure 4.  Angiotensin-converting enzyme and ACE2 immunogold labelling in glomeruli from 8-week-old mice Angiotensin-converting enzyme labelled with 10 nm gold particles is localized in endothelial cells (A, arrow). Angiotensin-converting enzyme 2 labelled with 15 nm gold particles is distributed in podocyte foot processes (B, arrows). GBM, glomerular basement membrane. Original magnification, x30 000 (JEOL 1220 transmission electron microscopy). Reproduced from Ye et al. (2006), with permission.

In kidneys from healthy control subjects, Lely and co-workers have found ACE2 expression in tubular, glomerular visceral and parietal epithelial cells, as well as in vascular muscular smooth muscle cells and the endothelium of interlobular arteries (Lely et al. 2004). In agreement with our findings in mice (Ye et al. 2006), these authors did not find ACE2 expression in glomerular endothelium (Lely et al. 2004).

	Angiotensin-converting enzyme 2 in cultured kidney cells

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
In stably transfected polarized Madin–Darby canine kidney (MDCKII) cells, which are renal tubular epithelial cells, ACE2 predominantly localizes to apical membranes (92%), in contrast to ACE, which is found on both apical (55%) and basolateral surfaces (45%; Warner et al. 2005). The high level of both enzymes, ACE and ACE2, in proximal tubule cells may help directly counterbalance Ang II levels by balancing the formation and degradation of local Ang II, respectively. It should be noted that in rat kidney, ACE2 and Ang(1–7) have been co-localized immunohistochemically to the proximal tubule (Brosnihan et al. 2003). In addition, Su and co-workers demonstrated the presence of Mas receptor, identified as a receptor for Ang(1–7), in rat proximal tubular cells (Su et al. 2006). Angiotensin(1–7) can inhibit Ang II-mediated phosphorylation of mitogen-activated protein (MAP) kinases and can partly suppress Ang II-stimulated increases in transforming growth factor-β (Su et al. 2006). This suggests that ACE2-mediated production of Ang(1–7) may counteract the effects of locally generated Ang II in the proximal tubule. This may help protect against the development of progressive tubulointerstitial fibrosis, as suggested previously (Ye et al. 2004; Su et al. 2006).

Several studies have examined the renin–angiotensin system (RAS) in glomerular epithelial cells (podocytes; Racusen et al. 1984; Durvasula et al. 2004; Hoffmann et al. 2004; Liebau et al. 2006; Velez et al. 2007). Researchers in our laboratory and others have recently demonstrated the presence of ACE2 in cultured podocytes (Wysocki et al. 2006a; Velez et al. 2007). These studies examined the processing of angiotensin substrates in immortalized cultured mouse podocytes (Wysocki et al. 2006a; Velez et al. 2007). Velez and co-workers further showed that podocytes express a functional intrinsic RAS characterized by neprilysin, aminopeptidase A, ACE2 and renin activities, which predominantly lead to formation of Ang(1–7) and Ang(1–9) (Velez et al. 2007). The abundance of ACE2 in podocytes and its anatomical localization within the glomerular filtration barrier, in close proximity to the glomerular endothelial cells, may be important in regulating Ang II levels by degrading local Ang II or promoting the conversion of filtered Ang II to the vasodilator peptide, Ang(1–7) (Velez et al. 2007). Velez and co-workers found modest ACE activity in podocytes, although only after cells were incubated with a higher concentration of Ang I (Velez et al. 2007). Researchers in our laboratory did not find ACE protein expression, either by Western blotting or by immunofluorescence, in cultured mouse podocytes (Wysocki et al. 2006a). Moreover, glomerular ACE did not co-localize with podocyte markers, such as synaptopodin, podocin and nephrin (Ye et al. 2006). We think, therefore, that the podocyte must generate Ang II by an ACE-independent pathway. We suggest that ACE2 in the podocyte is a key enzyme for Ang II degradation to Ang(1–7). Moreover, ACE2 also degrades Ang I to Ang(1–9). Thus, angiotensin peptides can be degraded quite efficiently within the podocyte, but not in endothelial cells. If ACE2 is decreased in the glomeruli in certain pathological states this would lead to impaired Ang peptide degradation, with their consequent accumulation within the glomerulus.

	Angiotensin-converting enzyme 2 deficiency in the kidney

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
Recent studies in mice with genetic ACE2 ablation or using a pharmacological ACE2 inhibitor named MLN-4760 have shed new light on the role of ACE2 in kidney disease (Oudit et al. 2006; Ye et al. 2006; Soler et al. 2007; Wong et al. 2007). Genetic ACE2 ablation in male mice (ACE2^–/y) leads to age-dependent development of glomerular mesangial expansion with increased deposition of fibrillar collagens I/III and the extracellular matrix protein fibronectin. Glomerular vascular injury was limited to the microvasculature of the glomerular capillary tuft and the preglomerular afferent arteriole, with arteriolar hyalinosis and micoraneurysm formation (Oudit et al. 2006). The development of glomerulosclerosis was associated with impairment in the glomerular filtration barrier such that urinary albumin was increased in male Ace2 mutant mice, but there was no biochemical evidence of azotemia (Oudit et al. 2006). In contrast, female Ace2 mutant (ACE2^–/–) mice were relatively protected. The glomerular injury and the development of glomerulosclerosis and albuminuria in Ace2 male mutant mice were prevented by treatment with the angiotensin II type 1 receptor blocker, irbesartan (Oudit et al. 2006). Interestingly, mean systemic blood pressure was not increased in this knockout. In fact, in 1-year-old ACE2^–/y mice, blood pressure was lower compared with ACE2^+/y mice. Fasting blood glucose was similar in age-matched littermate ACE2^–/y and ACE2^+/y mice (Oudit et al. 2006). These observations show that glomerular pathological changes in male ACE2^–/y mice can occur without either a systemic elevation of blood pressure or a high blood glucose when ACE2 is absent (Oudit et al. 2006).

In a study by Gurley and co-workers in mice on the C57BL/6 background, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 had no effect on baseline blood pressure in 129/SvEv mice (Gurley et al. 2006). These findings suggest that genetic background can significantly modify the impact of ACE2 on blood pressure homeostasis. After acute Ang II infusion, plasma concentrations of Ang II increased almost threefold in ACE2-deficient mice compared with control animals. Moreover, in Ang II-dependent hypertension, blood pressure was substantially higher in the ACE2-deficient mice than in wild-type mice (Gurley et al. 2006). This study suggested that ACE2 is a functional component of the RAS, metabolizing Ang II and thereby contributing to regulation of blood pressure. In an elegant study using a lentiviral system to increase ACE2 expression, Raizada's group found that this approach is capable of decreasing blood pressure in spontaneously hypertensive rats (Diez-Freire et al. 2006). Similarly, preliminary data from our group show that the administration of recombinant ACE2 is capable of preventing Ang II-induced hypertension (Ye et al. 2007).

	Angiotensin-converting enzyme 2 and diabetic nephropathy

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
The RAS plays an important role in the pathophysiology of many progressive diseases, including cardiovascular and kidney diseases (Hollenberg & Raij, 1993; Nicholls et al. 1998; Taal & Brenner, 2000; Carey & Siragy, 2003). Angiotensin II directly constricts vascular smooth muscle cells, enhances myocardial contractility, stimulates aldosterone production, increases sympathetic nervous system activity and stimulates thirst and salt appetite (Kobori et al. 2007). Locally produced Ang II induces inflammation, cell growth, mitogenesis, apoptosis, migration and differentiation, and regulates the gene expression of bioactive substances, all of which might contribute to tissue injury (Kobori et al. 2007). Overactivity of the RAS is generally believed to be involved in the progression of diabetic kidney disease (Hollenberg & Raij, 1993; Nicholls et al. 1998; Taal & Brenner, 2000; Carey & Siragy, 2003).

Researchers in our laboratory have studied renal ACE and ACE2 expression in the glomerulus from young female genetically obese, diabetic mice (db/db; Ye et al. 2006). At the age of 8 weeks, an early phase of diabetes, this model presents increased urinary albumin excretion without renal pathology by light microscopy (Sharma et al. 2003; Breyer et al. 2005; Ye et al. 2006). Glomerular immunostaining for ACE2 is greatly attenuated in db/db mice as compared with the control db/m mice (Ye et al. 2006). Angiotensin-converting enzyme, by contrast, was increased in glomeruli from db/db mice (Ye et al. 2006; Fig. 5). Of note, similar results in terms of increased glomerular ACE were found in streptozotocin (STZ)-treated rats and mice (Anderson et al. 1993; Tikellis et al. 2003; Soler et al. 2007). Since, in mouse glomeruli, ACE is expressed in endothelial cells but not in podocytes or mesangial cells, it seems that the increased ACE staining observed in the glomeruli from db/db mice reflects an increase at the level of glomerular endothelial cells (Ye et al. 2006). Since ACE2 is expressed in podocytes, the decreased ACE2 glomerular expression in young db/db mice is likely to reflect a decrease in protein expression at the level of the podocyte cells (Ye et al. 2006). Further studies performed by our group demonstrated that this pattern of glomerular staining for ACE and ACE2 in young diabetic mice is also observed in mice with established nephropathy (Soler et al. 2006). Thus, it seems that in the diabetic glomerulus, a combination of high ACE and low ACE2 is apt to increase Ang II formation, while decreasing Ang II degradation (Ye et al. 2006). It should be noted that the expression of nephrin, a key protein of the glomerular podocyte–slit diaphram complex is reduced in glomeruli from diabetic rats and mice (Forbes et al. 2002; Sung et al. 2006). This decrease in nephrin protein expression may be associated with increased albuminuria and may be related, in part, to altered trafficking of nephrin by angiotensin II in the podocyte (Macconi et al. 2006).

View larger version (144K): [in this window] [in a new window]   Figure 5.  Immunohistochemistry of ACE (A and B) and ACE2 (C and D) in kidney sections from db/m (A and C) and db/db 8-week-old mice (B and D), showing an example of glomerular ACE and ACE2 staining In young db/db mice, ACE staining within glomerular tuft (B, bold arrow) is more intense than in non-diabetic db/m control mice (A, bold arrow). The reverse pattern is seen for ACE2 staining within glomeruli, where ACE2 staining is less pronounced in diabetic mice (D, bold arrow) than in control mice (C, bold arrow). The ACE2 staining in glomerular parietal epithelium also is shown (D, double arrows). Reproduced from Ye et al. (2006), with permission.

Researchers in our laboratory had also studied the effect of chronic pharmacological ACE2 inhibition using a specific ACE2 inhibitor, MLN-4760, given for several weeks to diabetic mice (Ye et al. 2006; Soler et al. 2007). In db/db mice, the administration MLN-4760 for 16 weeks resulted in increased albuminuria and glomerular deposition of fibronectin that was prevented by co-administration of an Ang II type 1 receptor blocker (Ye et al. 2006). In another model of diabetes, the STZ-treated mouse, ACE2 inhibition for 4 weeks increased albuminuria and worsened glomerular injury, namely mesangial matrix expansion (Fig. 6). Furthermore, chronic pharmacological ACE2 inhibition with MLN-4760 was associated with enhanced ACE expression in both glomeruli and vasculature (Soler et al. 2007). This suggests that a dual mechanism of RAS activation in the glomerulus and renal vasculature may occur during chronic ACE2 inhibition, i.e. decreased degradation of Ang II, which would result in Ang II accumulation, and increased ACE expression, which would result in enhanced formation of Ang II. In addition, decreased degradation of Ang II is apt to result in reduced formation of Ang(1–7). Interestingly, renal medulla and papilla were atrophic in STZ-induced diabetic mice treated with MLN-4760 (Soler et al. 2007). It should be noted that in ACE knockout mice, marked medullary and papillary atrophy are prominent findings (Esther et al. 1996). The observed decrease in ACE tubular activity and in STZ-induced diabetic mice treated with MLN-4760 may be a mechanism involved in the atrophic tubular lesions seen in the medulla and papilla (Soler et al. 2007).

View larger version (67K): [in this window] [in a new window]   Figure 6.  Kidney sections from non-diabetic mice (A), STZ-treated mice given vehicle (B) and STZ-treated mice receiving MLN-4760 (C) Periodic acid–Schiff staining in glomerulus (original magnification x600). Streptozotocin-treated mice given vehicle (B) show mild mesangial expansion and hypercellularity compared with non-diabetic mice (A). Streptozotocin-treated mice given MLN-4760 (C) show increased mesangial expansion compared with STZ-treated mice given vehicle (B). Reproduced from Soler et al. (2007), with permission.

	Conclusion

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
In summary, ACE2 is highly expressed in the kidney and it is distributed in glomerular, tubular and vascular structures. Glomerular ACE2 expression is decreased in models of diabetic kidney disease. Furthermore, pharmacological ACE2 inhibition or genetic ACE2 ablation in the diabetic ‘milieu’ increases urinary albumin excretion and worsens glomerular injury. We suggest that ACE2 inhibition results in decreased degradation of Ang II, which in turn results in intraglomerular Ang II accumulation. Since ACE2 degrades the vasoactive and proliferative peptide, Ang II, a modification of ACE2 levels by stimulating its expression or exogenous administration of ACE2 may provide a therapeutic approach in several kidney diseases, including diabetic nephropathy. In this regard, experimental studies are urgently needed to further delineate a beneficial effect of increasing ACE2 expression on renal damage.

	References

Top Abstract Introduction Localization of ACE2 in... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Angiotensin-converting enzyme 2... Conclusion References

 
Acharya KR, Sturrock ED, Riordan JF & Ehlers MR (2003). Ace revisited: a new target for structure-based drug design. Nat Rev Drug Discov 2, 891–902.[CrossRef][Medline]

Anderson S, Jung FF & Ingelfinger JR (1993). Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Physiol Renal Physiol 265, F477–F486.[Abstract/Free Full Text]

Breyer MD, Bottinger E, Brosius FC 3rd, Coffman TM, Harris RC, Heilig CW & Sharma K (2005). Mouse models of diabetic nephropathy. J Am Soc Nephrol 16, 27–45.[Abstract/Free Full Text]

Brosnihan KB, Li P & Ferrario CM (1996). Angiotensin-(1–7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension 27, 523–528.[Abstract/Free Full Text]

Brosnihan KB, Neves LA, Joyner J, Averill DB, Chappell MC, Sarao R, Penninger J & Ferrario CM (2003). Enhanced renal immunocytochemical expression of ANG-(1–7) and ACE2 during pregnancy. Hypertension 42, 749–753.[Abstract/Free Full Text]

Carey RM & Siragy HM (2003). The intrarenal renin-angiotensin system and diabetic nephropathy. Trends Endocrinol Metab 14, 274–281.[CrossRef][Medline]

Carvalho MB, Duarte FV, Faria-Silva R, Fauler B, da Mata Machado LT, de Paula RD, Campagnole-Santos MJ & Santos RA (2007). Evidence for Mas-mediated bradykinin potentiation by the angiotensin-(1–7) nonpeptide mimic AVE 0991 in normotensive rats. Hypertension 50, 762–767.[Abstract/Free Full Text]

Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Backx PH, Yagil Y & Penninger JM (2002). Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417, 822–828.[CrossRef][Medline]

Diez-Freire C, Vazquez J, Correa de Adjounian MF, Ferrari MF, Yuan L, Silver X, Torres R & Raizada MK (2006). ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol Genomics 27, 12–19.[CrossRef][Medline]

Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE & Acton S (2000). A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 87, E1–E9.[Medline]

Doobay MF, Talman LS, Obr TD, Tian X, Davisson RL & Lazartigues E (2007). Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 292, R373–R381.[Abstract/Free Full Text]

Durvasula RV, Petermann AT, Hiromura K, Blonski M, Pippin J, Mundel P, Pichler R, Griffin S, Couser WG & Shankland SJ (2004). Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65, 30–39.[CrossRef][Medline]

Esther CR Jr, Howard TE, Marino EM, Goddard JM, Capecchi MR & Bernstein KE (1996). Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 74, 953–965.[Medline]

Forbes JM, Bonnet F, Russo LM, Burns WC, Cao Z, Candido R, Kawachi H, Allen TJ, Cooper ME, Jerums G & Osicka TM (2002). Modulation of nephrin in the diabetic kidney: association with systemic hypertension and increasing albuminuria. J Hypertens 20, 985–992.[CrossRef][Medline]

Gembardt F, Sterner-Kock A, Imboden H, Spalteholz M, Reibitz F, Schultheiss HP, Siems WE & Walther T (2005). Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents. Peptides 26, 1270–1277.[CrossRef][Medline]

Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N, Haystead TA, Donoghue M, Breitbart RE, Acton SL, Rockman HA & Coffman TM (2006). Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 116, 2218–2225.[CrossRef][Medline]

Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, Timens W, Turner AJ, Navis G & van Goor H (2007). The emerging role of ACE2 in physiology and disease. J Pathol 212, 1–11.[CrossRef][Medline]

Hamming I, Timens W, Bulthuis ML, Lely AT, Navis GJ & van Goor H (2004). Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 203, 631–637.[CrossRef][Medline]

Hoffmann S, Podlich D, Hahnel B, Kriz W & Gretz N (2004). Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol 15, 1475–1487.[Abstract/Free Full Text]

Hollenberg NK & Raij L (1993). Angiotensin-converting enzyme inhibition and renal protection. An assessment of implications for therapy. Arch Intern Med 153, 2426–2435.[Abstract]

Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C & Penninger JM (2005). Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436, 112–116.[CrossRef][Medline]

Kobori H, Ozawa Y, Satou R, Katsurada A, Miyata K, Ohashi N, Hase N, Suzaki Y, Sigmund CD & Navar LG (2007). Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice. Am J Physiol Renal Physiol 293, F938–F945.[Abstract/Free Full Text]

Konoshita T, Wakahara S, Mizuno S, Motomura M, Aoyama C, Makino Y, Kawai Y, Kato N, Koni I, Miyamori I & Mabuchi H (2006). Tissue gene expression of renin-angiotensin system in human type 2 diabetic nephropathy. Diabetes Care 29, 848–852.[Abstract/Free Full Text]

Lely AT, Hamming I, van Goor H & Navis GJ (2004). Renal ACE2 expression in human kidney disease. J Pathol 204, 587–593.[CrossRef][Medline]

Li N, Zimpelmann J, Cheng K, Wilkins JA & Burns KD (2005). The role of angiotensin converting enzyme 2 in the generation of angiotensin 1–7 by rat proximal tubules. Am J Physiol Renal Physiol 288, F353–F362.[Abstract/Free Full Text]

Liebau MC, Lang D, Bohm J, Endlich N, Bek MJ, Witherden I, Mathieson PW, Saleem MA, Pavenstadt H & Fischer KG (2006). Functional expression of the renin-angiotensin system in human podocytes. Am J Physiol Renal Physiol 290, F710–F719.[Abstract/Free Full Text]

Macconi D, Abbate M, Morigi M, Angioletti S, Mister M, Buelli S, Bonomelli M, Mundel P, Endlich K, Remuzzi A & Remuzzi G (2006). Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target for renoprotective intervention. Am J Pathol 168, 1073–1085.[Abstract/Free Full Text]

Nicholls MG, Richards AM & Agarwal M (1998). The importance of the renin-angiotensin system in cardiovascular disease. J Hum Hypertens 12, 295–299.[CrossRef][Medline]

Oudit GY, Herzenberg AM, Kassiri Z, Wong D, Reich H, Khokha R, Crackower MA, Backx PH, Penninger JM & Scholey JW (2006). Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol 168, 1808–1820.[Abstract/Free Full Text]

Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, Shaw T, Warner FJ, Zuilli A, Burrell LM & Angus PW (2005). Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 54, 1790–1796.[Abstract/Free Full Text]

Racusen LC, Prozialeck DH & Solez K (1984). Glomerular epithelial cell changes after ischemia or dehydration. Possible role of angiotensin II. Am J Pathol 114, 157–163.[Abstract]

Rella M, Elliot JL, Revett TJ, Lanfear J, Phelan A, Jackson RM, Turner AJ & Hooper NM (2007). Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE. BMC Genomics 8, 194.[CrossRef][Medline]

Sampaio WO, Henrique de Castro C, Santos RA, Schiffrin EL & Touyz RM (2007). Angiotensin-(1–7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension 50, 1093–1098.[Abstract/Free Full Text]

Santos RA, Campagnole-Santos MJ & Andrade SP (2000). Angiotensin-(1–7): an update. Regul Pept 91, 45–62.[CrossRef][Medline]

Santos SH, Fernandes LR, Mario EG, Ferreira AV, Porto LC, Alvarez-Leite JI, Botion LM, Bader M, Alenina N & Santos RA (2007). Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes 57, 340–347.[CrossRef][Medline]

Sharma K, McCue P & Dunn SR (2003). Diabetic kidney disease in the db/db mouse. Am J Physiol Renal Physiol 284, F1138–F1144.[Abstract/Free Full Text]

Soler MJ, Wysocki J, Sowers K, Ye M & Batlle D (2006). Expression of ACE/ACE2 in renal tubules and glomerulus from db/db mice with established nephropathy. J Am Soc Nephrol 17, 123A–124A (Abstract).[CrossRef]

Soler MJ, Wysocki J, Ye M, Lloveras J, Kanwar Y & Batlle D (2007). ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int 72, 614–623.[CrossRef][Medline]

Su Z, Zimpelmann J & Burns KD (2006). Angiotensin-(1–7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. Kidney Int 69, 2212–2218.[CrossRef][Medline]

Sung SH, Ziyadeh FN, Wang A, Pyagay PE, Kanwar YS & Chen S (2006). Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol 17, 3093–3104.[Abstract/Free Full Text]

Taal MW & Brenner BM (2000). Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 57, 1803–1817.[CrossRef][Medline]

Tikellis C, Johnston CI, Forbes JM, Burns WC, Burrell LM, Risvanis J & Cooper ME (2003). Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension 41, 392–397.[Abstract/Free Full Text]

Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G & Turner AJ (2000). A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275, 33238–33243.[Abstract/Free Full Text]

Turner AJ & Hooper NM (2002). The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 23, 177–183.[CrossRef][Medline]

Valdes G, Neves LA, Anton L, Corthorn J, Chacon C, Germain AM, Merrill DC, Ferrario CM, Sarao R, Penninger J & Brosnihan KB (2006). Distribution of angiotensin-(1–7) and ACE2 in human placentas of normal and pathological pregnancies. Placenta 27, 200–207.[CrossRef][Medline]

Velez JC, Bland AM, Arthur JM, Raymond JR & Janech MG (2007). Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes. Am J Physiol Renal Physiol 293, F398–F407.[Abstract/Free Full Text]

Warner FJ, Lew RA, Smith AI, Lambert DW, Hooper NM & Turner AJ (2005). Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J Biol Chem 280, 39353–39362.[Abstract/Free Full Text]

Wong DW, Oudit GY, Reich H, Kassiri Z, Zhou J, Liu QC, Backx PH, Penninger JM, Herzenberg AM & Scholey JW (2007). Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol 171, 438–451.[Abstract/Free Full Text]

Wysocki J, Soler M, Ye M & Batlle D (2006a). ACE2 is critically important for angiotensin II metabolism in podocytes. J Am Soc Nephrol 17, TH-PO877.293A.

Wysocki J, Ye M, Soler MJ, Gurley SB, Xiao HD, Bernstein KE, Coffman TM, Chen S & Batlle D (2006b). ACE and ACE2 activity in diabetic mice. Diabetes 55, 2132–2139.[CrossRef][Medline]

Xie X, Chen J, Wang X, Zhang F & Liu Y (2006). Age- and gender-related difference of ACE2 expression in rat lung. Life Sci 78, 2166–2171.[CrossRef][Medline]

Ye M, Wysocki J, Naaz P, Salabat MR, LaPointe MS & Batlle D (2004). Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice: a renoprotective combination? Hypertension 43, 1120–1125.[Abstract/Free Full Text]

Ye M, Wysocki J, Rodriguez E, Schuster M, Loibner H, Penninger J & Batlle D (2007). Recombinant ACE2 attenuates angiotensin II induced hypertension. In 61st Annual High Blood Pressure Research Conference, Westin La Paloma. Tucson, AZ, USA.

Ye M, Wysocki J, William J, Soler MJ, Cokic I & Batlle D (2006). Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol 17, 3067–3075.[Abstract/Free Full Text]

Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, Wang H, Lin S, Kanwar YS & Makino H (2001). Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J Biol Chem 276, 17132–17139.[Abstract/Free Full Text]

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