Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice

Angiotensin-converting enzyme 2 (ACE2) degrades angiotensin II to angiotensin-(1–7) and is expressed in podocytes. Here we overexpressed ACE2 in podocytes in experimental diabetic nephropathy using transgenic methods where a nephrin promoter drove the expression of human ACE2. Glomeruli from these mice had significantly increased mRNA, protein, and activity of ACE2 compared to wild-type mice. Male mice were treated with streptozotocin to induce diabetes. After 16 weeks, there was no significant difference in plasma glucose levels between wild-type and transgenic diabetic mice. Urinary albumin was significantly increased in wild-type diabetic mice at 4 weeks, whereas albuminuria in transgenic diabetic mice did not differ from wild-type nondiabetic mice. However, this effect was transient and by 16 weeks both transgenic and nontransgenic diabetic mice had similar rates of proteinuria. Compared to wild-type diabetic mice, transgenic diabetic mice had an attenuated increase in mesangial area, decreased glomerular area, and a blunted decrease in nephrin expression. Podocyte numbers decreased in wild-type diabetic mice at 16 weeks, but were unaffected in transgenic diabetic mice. At 8 weeks, kidney cortical expression of transforming growth factor-β1 was significantly inhibited in transgenic diabetic mice as compared to wild-type diabetic mice. Thus, the podocyte-specific overexpression of human ACE2 transiently attenuates the development of diabetic nephropathy. Angiotensin-converting enzyme 2 (ACE2) degrades angiotensin II to angiotensin-(1–7) and is expressed in podocytes. Here we overexpressed ACE2 in podocytes in experimental diabetic nephropathy using transgenic methods where a nephrin promoter drove the expression of human ACE2. Glomeruli from these mice had significantly increased mRNA, protein, and activity of ACE2 compared to wild-type mice. Male mice were treated with streptozotocin to induce diabetes. After 16 weeks, there was no significant difference in plasma glucose levels between wild-type and transgenic diabetic mice. Urinary albumin was significantly increased in wild-type diabetic mice at 4 weeks, whereas albuminuria in transgenic diabetic mice did not differ from wild-type nondiabetic mice. However, this effect was transient and by 16 weeks both transgenic and nontransgenic diabetic mice had similar rates of proteinuria. Compared to wild-type diabetic mice, transgenic diabetic mice had an attenuated increase in mesangial area, decreased glomerular area, and a blunted decrease in nephrin expression. Podocyte numbers decreased in wild-type diabetic mice at 16 weeks, but were unaffected in transgenic diabetic mice. At 8 weeks, kidney cortical expression of transforming growth factor-β1 was significantly inhibited in transgenic diabetic mice as compared to wild-type diabetic mice. Thus, the podocyte-specific overexpression of human ACE2 transiently attenuates the development of diabetic nephropathy. Angiotensin-converting enzyme 2 (ACE2), a recently discovered member of the renin–angiotensin system, has a single catalytic domain and shares 40% homology with ACE.1.Donoghue M. Hsieh F. Baronas E. et al.A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ Res. 2000; 87: e1-e9Crossref PubMed Google Scholar,2.Tipnis S. Hooper N. Hyde R. et al.A human homolog of angiotensin-converting enzyme.J Biol Chem. 2000; 275: 33238-33243Crossref PubMed Scopus (1639) Google Scholar Despite this similarity, ACE2 activity is not affected by ACE inhibitors, nor does it generate angiotensin (Ang) II. On the contrary, ACE2 degrades Ang II to Ang-(1–7), a peptide that antagonizes Ang II signaling.3.Freeman E.J. Chisolm G.M. Ferrario C.M. et al.Angiotensin-(1-7) inhibits vascular smooth muscle cell growth.Hypertension. 1996; 28: 104-108Crossref PubMed Scopus (261) Google Scholar, 4.Sampaio W.O. Henrique de Castro C. Santos R.A. et al.Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells.Hypertension. 2007; 50: 1093-1098Crossref PubMed Scopus (211) Google Scholar, 5.Su Z. Zimpelmann J. Burns K.D. Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells.Kidney Int. 2006; 69: 2212-2218Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar ACE2 also degrades Ang I to Ang-(1–9) that is subsequently converted to Ang-(1–7) by ACE.6.Rice G. Thomas D. Grant P. et al.Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism.Biochem J. 2004; 383: 45-51Crossref PubMed Scopus (465) Google Scholar Because of these properties, ACE2 has been postulated to be an endogenous renoprotective enzyme.7.Ye M. Wysocki J. Naaz P. et al.Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice: a renoprotective combination?.Hypertension. 2004; 43: 1120-1125Crossref PubMed Scopus (196) Google Scholar ACE2 may be involved in the pathogenesis of diabetic nephropathy. Pharmacological inhibition of ACE2 in streptozotocin (STZ)-induced diabetic mice causes increased albuminuria and expansion of the glomerular matrix.8.Soler M. Wysocki J. Ye M. et al.ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice.Kidney Int. 2007; 72: 614-623Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar In Akita mice, a model of type 1 diabetes, deletion of the ACE2 gene has been reported to exacerbate albuminuria, associated with increased mesangial matrix deposition, glomerular basement membrane thickening, and glomerulosclerosis, without significant changes in blood pressure (BP).9.Wong D. Oudit G. Reich H. et al.Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury.Am J Pathol. 2007; 171: 438-451Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar Recently, administration of human recombinant ACE2 to diabetic Akita mice significantly reduced albuminuria, associated with decreased BP.10.Oudit G. Liu G. Zhong J. et al.Human recombinant ACE2 reduces the progression of diabetic nephropathy.Diabetes. 2010; 59: 529-538Crossref PubMed Scopus (243) Google Scholar Similarly, intravenous administration of recombinant adenovirus carrying the mouse ACE2 gene to rats with STZ-diabetes was associated with diminished albuminuria and glomerulosclerosis, although systolic BP was also reduced.11.Liu C.X. Hu Q. Wang Y. et al.Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition.Mol Med. 2011; 17: 59-69Crossref PubMed Scopus (21) Google Scholar Accordingly, there is increasing interest in the potential therapeutic action of ACE2 amplification to treat diabetic nephropathy, as recently reviewed.12.Batlle D. Wysocki J. Soler M.J. et al.Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy.Kidney Int. 2011; 81: 520-528Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Glomerular podocytes are terminally differentiated epithelial cells that are key components of the selective permeability barrier of the glomerular basement membrane.13.Pavenstadt H. Kriz W. Kretzler M. Cell biology of the glomerular podocyte.Physiol Rev. 2003; 83: 253-307Crossref PubMed Scopus (1203) Google Scholar Podocyte apoptosis and detachment are directly correlated with the progression of diabetic nephropathy.14.Toyoda M. Najafian B. Kim Y. et al.Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy.Diabetes. 2007; 56: 2155-2160Crossref PubMed Scopus (209) Google Scholar ACE2 has been localized to the podocyte, and podocyte ACE2 expression decreases in experimental diabetes.15.Ye M. Wysocki J. Soler M. et al.Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: implications for albuminuria in diabetes.J Am Soc Nephrol. 2006; 17: 3067-3075Crossref PubMed Scopus (376) Google Scholar However, there is no direct evidence regarding ACE2 overexpression in the podocyte as a protector against the development of diabetic nephropathy. In the current study, transgenic (TG) mice were generated that selectively overexpress human ACE2 in the podocyte to address this question. Specifically, we wished to examine the hypothesis that a podocyte-specific ACE2 transgene could protect against glomerular injury in the STZ model of diabetes, independent of changes in BP. TG mice with podocyte-specific overexpression of human ACE2 were characterized by reverse transcriptase–PCR, immunoblot analysis of isolated glomeruli, direct immunofluorescence, and measurement of glomerular ACE2 activity. By real-time reverse transcriptase–PCR, human ACE2 mRNA was readily detected in glomeruli from TG mice, at a level ∼50-fold higher than in kidney cortex (Figure 1a). In contrast, the levels of endogenous mouse ACE2 mRNA in TG mice were significantly lower in glomeruli than in kidney cortex (Figure 1b). In wild-type (WT) mice, levels of endogenous mouse ACE2 mRNA were also significantly lower in glomeruli than kidney cortex (n=4, not shown). In TG mice, expression of endogenous mouse ACE2 in kidney cortex was not significantly affected by the presence of the human ACE2 transgene (relative levels of mouse ACE2 mRNA, TG vs. WT mice: 1.8±1.1-fold, P=not significant, n=3). Similarly, glomerular expression of endogenous mouse ACE2 was not affected by the human ACE2 transgene (WT: 1.37±0.19 vs. TG: 1.65±0.33 arbitrary units, P=not significant, n=2–4). Expression of the human ACE2 transgene was also not detected at significant levels in the heart, brain, liver, spleen, or lung (Figure 1a). In glomerular isolates from TG mice, the human ACE2 protein was detected by immunoblot as a single protein band of ∼120kDa, compared with the endogenous mouse ACE2 at ∼100kDa (Figure 1c). In TG mice, the human ACE2 protein was not readily detected in kidney cortical homogenates (Figure 1c). By immunofluorescence of kidney cortical tissue, TG mice demonstrated positive glomerular staining for the hemagglutinin epitope tag, which colocalized with the podocyte protein synaptopodin (Figure 1d). In freshly isolated glomeruli, ACE2 enzymatic activity was significantly increased in TG mice as compared with WT mice (Figure 1e: 2.82-fold increase in TG vs. WT mice, P<0.02, n=9–10). Table 1 depicts whole animal data regarding body and organ weights, and plasma glucose. WT and TG mice treated with STZ (WT-STZ and TG-STZ, respectively) developed severe diabetes, with significantly increased plasma glucose compared with vehicle-treated mice, and with no significant difference between the two STZ groups. TG mice had lower body weights than WT mice matched for age. However, both WT-STZ and TG-STZ mice experienced weight loss, and renal hypertrophy, inferred from increased kidney weight to body weight ratio (P<0.001 vs. In contrast, there was no difference in weight to body weight the groups. Despite the levels of plasma diabetic mice did not as by at 16 weeks, and of shown). was for mice in the study, with no significant the groups. In TG-STZ mice, glomerular ACE2 activity significantly increased 16 weeks as compared with WT-STZ By glomerular ACE2 expression was significantly increased in TG mice compared with WT mice and this increase 16 weeks STZ (Figure Glomerular human ACE2 protein expression by immunoblot also at 16 weeks (Figure 1c). At this in contrast, plasma ACE2 activity was decreased in TG-STZ mice compared with WT-STZ mice vs. However, both diabetic had higher plasma ACE2 activity compared with animal vs. vs. WT and vs. vs. WT and vs. vs. WT and vs. WT and glucose vs. WT and vs. WT and body kidney TG-STZ, transgenic wild-type are vs. WT and vs. vs. vs. WT and vs. WT and in a angiotensin-converting enzyme 2 (ACE2) activity. depicts plasma ACE2 enzymatic activity from wild-type transgenic wild-type and transgenic mice at 16 are vs. WT and vs. WT and vs. body kidney TG-STZ, transgenic wild-type are At 16 weeks, there were no significant in plasma protein, or between WT-STZ and TG-STZ mice shown). WT-STZ mice had significant in compared with BP was the and to be higher in both of STZ mice compared with mice, but the difference was not significant the (Figure BP did not significantly differ between WT-STZ and TG-STZ mice at in the study, nor did it differ between WT and TG mice (Figure At 16 weeks, glomerular was significantly higher in WT-STZ and TG-STZ mice compared with WT and TG mice, but there was no difference between the two STZ (Figure At 4 weeks, WT-STZ mice had significantly increased levels of albuminuria as compared with vehicle-treated mice (Figure In contrast, TG-STZ mice had no increase in albuminuria at 4 weeks vs. However, there was no significant difference in albuminuria between WT-STZ and TG-STZ mice at 8 weeks vs. P=not significant, Similarly, at 16 weeks, both WT-STZ and TG-STZ mice had increased levels of albuminuria, with no significant difference between the two (Figure staining of in mice compared with nondiabetic mice (Figure analysis was kidney at 8 and 16 At 8 weeks, WT-STZ mice and TG-STZ mice demonstrated in mesangial and glomerular compared with vehicle-treated mice (Figure increase in mesangial area, was significantly attenuated in TG-STZ mice. At 16 weeks, mesangial and glomerular were significantly increased in WT-STZ and TG-STZ as compared with nondiabetic mice (Figure Glomerular was significantly diminished in TG-STZ mice compared with WT-STZ mice (Figure of podocyte angiotensin-converting enzyme 2 (ACE2) overexpression mesangial and glomerular at 16 mesangial and glomerular at 16 weeks in wild-type transgenic wild-type and transgenic mice. at 16 are glomeruli of vs. WT and vs. WT and was no significant difference between WT-STZ and TG-STZ mice. Glomerular at 16 are glomeruli of vs. WT and vs. WT and vs. glomeruli in and TG-STZ mice at 16 Glomerular and increased mesangial staining is in STZ as compared with mice. Expression of the podocyte protein nephrin was by and In kidney cortical from WT-STZ mice, nephrin expression by immunoblot was significantly decreased at 8 weeks as compared with WT mice (Figure TG-STZ mice, in contrast, no significant difference in nephrin expression compared with TG although levels were Similarly, at 16 weeks, nephrin expression was significantly reduced in WT-STZ mice compared with WT mice, whereas nephrin levels did not significantly differ between TG and TG-STZ mice (Figure immunofluorescence analysis at 8 and 16 weeks a similar of glomerular nephrin expression as the (Figure In whereas nephrin expression was significantly reduced in WT-STZ mice, there was no significant difference in nephrin expression between TG and TG-STZ mice, although TG mice to lower expression than WT expression at 8 and 16 weeks by analysis of nephrin expression by immunofluorescence in wild-type transgenic wild-type and transgenic mice at 8 are glomeruli from to 8 mice vs. was no significant difference between TG and TG-STZ mice. glomerular nephrin expression at 8 weeks are staining is also nephrin expression by immunofluorescence at 16 are glomeruli from to mice vs. glomerular nephrin expression at 16 weeks are staining is also By immunofluorescence, glomerular synaptopodin expression was not significantly affected at 8 weeks, although there was a for reduced expression in WT-STZ and TG-STZ mice (Figure However, at 16 weeks, expression of synaptopodin was significantly reduced in WT-STZ mice compared with or TG-STZ mice (Figure Podocyte numbers were at 8 and 16 weeks by glomerular staining for At 8 weeks, both WT-STZ and TG-STZ mice had significantly decreased podocyte compared with mice (Figure In TG mice, podocyte was lower than in WT mice, and the decrease with STZ was compared with WT-STZ mice. At 16 weeks, WT-STZ mice a significant decrease in podocyte compared with vehicle-treated mice. In contrast, TG-STZ mice did not a significant decrease in podocytes as compared with nondiabetic mice (Figure in protein expression of the transforming growth factor-β1 was significantly increased in kidney from WT-STZ mice at 8 weeks compared with nondiabetic mice. In contrast, TG-STZ mice no increase in cortical at 8 At 16 weeks, expression of was increased in both WT-STZ and TG-STZ mice, with no significant difference between the two groups. of this is that overexpression of human ACE2 in the glomerular podocyte attenuates the development of nephropathy in mouse was by a in the development of albuminuria, independent of effect systolic evidence of renal an in mesangial and of glomerular at 16 of expression of the podocyte nephrin and of podocyte by ACE2 and in cortical expression at 8 In to against diabetic nephropathy, this model of ACE2 overexpression be to examine to and progression of in of glomerular are cells that a of the glomerular barrier to podocytes components of the renin–angiotensin of a angiotensin in podocytes by J PubMed Scopus Google Scholar, et of enzyme in mouse J 2007; PubMed Scopus Google Scholar, Kim et of the podocytes in Int. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar and ACE2 has been localized to the podocyte in glomeruli from diabetic mice by and M. Wysocki J. Soler M. et al.Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: implications for albuminuria in diabetes.J Am Soc Nephrol. 2006; 17: 3067-3075Crossref PubMed Scopus (376) Google Scholar of podocytes apoptosis to the pathogenesis of diabetic nephropathy. signaling may podocyte apoptosis in diabetes, of of H. Wang J. et in podocytes is a in the development of diabetic nephropathy in 2011; Scopus Google Scholar However, Ang II is as a key to podocyte with II type and of S. et of the protein 2 to angiotensin podocyte Int. 2011; Full Text Full Text PDF PubMed Scopus Google J. G. J. et II nephrin expression changes and podocyte J Nephrol. 28: PubMed Scopus Google Scholar In podocytes to of Ang II is which may to of a angiotensin in podocytes by J PubMed Scopus Google Scholar In the mouse model of type 2 diabetes, podocyte ACE2 expression is M. Wysocki J. Soler M. et al.Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: implications for albuminuria in diabetes.J Am Soc Nephrol. 2006; 17: 3067-3075Crossref PubMed Scopus (376) Google Scholar and renal from with diabetic nephropathy decreased glomerular ACE2 mRNA and protein Oudit et glomerular and tubular expression of ACE2 in with type 2 and kidney Int. Full Text Full Text PDF PubMed Scopus Google Scholar ACE2 degrades Ang II to Ang-(1–7), to or podocyte ACE2 could in Ang II ACE2 to of Ang-(1–7), which has been associated with of albuminuria in experimental C. et al.Angiotensin-(1-7) J 2007; PubMed Scopus Google Scholar glomerular TG mice that we in this did not compared with WT TG mice had lower body weights compared with WT mice matched for age. However, both WT-STZ and TG-STZ mice developed similar of plasma associated with of body kidney hypertrophy, glomerular and in systolic BP. human ACE2 was to the mouse nephrin promoter in these as nephrin gene expression is to H. R. P. et nephrin gene is expressed in and of the gene to and PubMed Scopus Google Scholar of evidence the that human ACE2 was selectively overexpressed in podocytes from TG mice. mRNA expression of the transgene in glomeruli from TG mice, at a level ∼50-fold higher than that in kidney whereas endogenous mouse ACE2 expression was lower in glomeruli than from TG mice, H. R. P. et nephrin gene is expressed in and of the gene to and PubMed Scopus Google did not significantly human ACE2 by the human ACE2 protein was detected in glomerular but not kidney as a protein of the ACE2 protein colocalized with synaptopodin by immunofluorescence, its presence in the ACE2 activity was significantly in glomeruli from TG mice, and activity glomerular expression by immunoblot and 16 weeks of In this nephrin expression decreases in diabetic E. S. et of gene expression and of nephrin in human diabetic nephropathy.Kidney Int. 2004; Full Text Full Text PDF PubMed Scopus Google S. G. E. et expression is reduced in human diabetic nephropathy: evidence for a for albumin and angiotensin 2003; PubMed Scopus Google Scholar and nephrin is associated with of that glomerular S. M. et and glomerular Am Soc Nephrol. PubMed Scopus Google Scholar data that the nephrin promoter and of the human ACE2 gene in TG-STZ mice, the presence of severe diabetes. selective overexpression of the human ACE2 gene in podocytes was not associated with changes in systolic BP. ACE2 activity did not increase the level of WT-STZ mice, in with the localized increase in ACE2 at the podocyte In WT-STZ mice, a significant increase in albuminuria at 4 weeks as compared with nondiabetic mice. In contrast, albumin in TG-STZ mice at 4 weeks did not differ from levels in mice. albuminuria levels in diabetic mouse model were significantly higher than reported by et Z. H. J. et of of mouse to diabetic nephropathy.Diabetes. PubMed Scopus Google Scholar in mice with is in albumin in mouse of diabetes, and using the we in this reported of albumin in mouse with N. R. et is for the development of diabetic nephropathy in PubMed Scopus Google S. Y. et of diabetic mice accelerates albuminuria, cell and changes in gene Nephrol. 2011; PubMed Scopus Google Scholar Despite the of albuminuria in TG-STZ mice, albuminuria increased to the level of WT-STZ mice at In diabetes, increased Ang II is to podocyte and Ang II reduces expression of the protein 2 in podocytes in and in associated with increased of inhibition of the and S. et of the protein 2 to angiotensin podocyte Int. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar TG-STZ mice were against albuminuria at 4 weeks, podocyte ACE2 activity may not been at to this Ang or podocyte may and to the in albuminuria in TG-STZ mice was associated with in of diabetic nephropathy. a significant decrease in mesangial at 8 weeks, with decreased glomerular at 16 expression of the podocyte nephrin and reported to be decreased in diabetic J. et attenuates glomerular and tubular in 2011; PubMed Scopus Google S. C. G. et al.Increased glomerular cell apoptosis in rats with streptozotocin-induced in the development of diabetic glomerular 2007; 50: PubMed Scopus Google Scholar was in TG-STZ mice. In TG mice, nephrin expression was decreased compared with WT mice, and with STZ did not induce a model the mouse nephrin promoter to induce podocyte-specific ACE2 the decrease in nephrin expression in TG mice could be of for between the nephrin gene and the against of podocyte was at 16 weeks, but not at 8 the expression of in kidney cortex was significantly attenuated in TG-STZ mice at 8 that this is of degradation of Ang II in the diabetic data the hypothesis that in the diabetic glomerular Ang II a in nephrin and synaptopodin and of which podocyte to and and which in is associated with increased of G. of the and in diabetic Rev. PubMed Scopus Google Scholar with this in rats with intravenous gene of ACE2 reduces kidney cortical levels of Ang and Ang-(1–7), associated with from glomerular C.X. Hu Q. Wang Y. et al.Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition.Mol Med. 2011; 17: 59-69Crossref PubMed Scopus (21) Google Scholar In rat mesangial of ACE2 inhibits Ang cell and C.X. Hu Q. Wang Y. et al.Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition.Mol Med. 2011; 17: 59-69Crossref PubMed Scopus (21) Google Scholar the of ACE2 may from a in Ang II levels in study, the of podocyte of Ang-(1–7) in TG mice Ang-(1–7) inhibits Ang signaling in proximal tubular cells and the E.J. Chisolm G.M. Ferrario C.M. et al.Angiotensin-(1-7) inhibits vascular smooth muscle cell growth.Hypertension. 1996; 28: 104-108Crossref PubMed Scopus (261) Google Scholar, 4.Sampaio W.O. Henrique de Castro C. Santos R.A. et al.Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells.Hypertension. 2007; 50: 1093-1098Crossref PubMed Scopus (211) Google Scholar, 5.Su Z. Zimpelmann J. Burns K.D. Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells.Kidney Int. 2006; 69: 2212-2218Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar its podocyte are In mesangial Ang-(1–7) has been reported to J. Burns K.D. Angiotensin-(1-7) in human mesangial J PubMed Scopus Google Scholar or Ang II M. et effect of angiotensin in type 2 diabetic nephropathy of J 2011; PubMed Scopus Google Scholar Thus, although overexpression of ACE2 in the podocyte has a renoprotective the of diminished levels of Ang II increased Ang-(1–7) this diabetic nephropathy, and the of overexpression of ACE2 progression In diabetes, TG mice with podocyte-specific overexpression of the human ACE2 protein are against the development of albuminuria and of podocyte and podocyte reduced glomerular and decreased kidney cortical expression. 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Full Text Full Text PDF PubMed Scopus Google Scholar was isolated from glomeruli and for real-time for ACE2. of the be in with cortical and glomeruli were for immunoblot analysis with to and of the be in glomerular was in mice at 16 weeks of study, using plasma as we M. Zimpelmann J. et of ACE2 and in a mouse model of kidney J 2010; PubMed Scopus Google Scholar At and 16 weeks was in Urinary albumin was using a albumin were with for at and were subsequently and were with for measurement of mesangial and glomerular Podocyte were by staining for D. et podocyte is a of glomerular than Am Soc Nephrol. PubMed Scopus Google Scholar and staining was for and synaptopodin using were in a the be in ACE2 activity in glomeruli and plasma was using a ACE2 as M. Zimpelmann J. et of ACE2 and in a mouse model of kidney J 2010; PubMed Scopus Google J. et expression of and angiotensin-converting enzyme 2 in the kidney of and J 2007; PubMed Scopus Google Scholar of the be in are as were using analysis was by analysis of by or two was of was for of the mouse and de for of the mouse was by from the of and the of to and by and to for human and mouse ACE2. is to the of the at

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