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Am J Physiol Renal Physiol 293: F1214-F1221, 2007. First published July 25, 2007; doi:10.1152/ajprenal.00162.2007
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Angiotensin II provokes podocyte injury in murine model of HIV-associated nephropathy

Hiroshi Ideura,1 Keiju Hiromura,1 Noriyuki Hiramatsu,1 Tetsuya Shigehara,1,2 Shigeru Takeuchi,1 Mai Tomioka,1 Toru Sakairi,1 Shin Yamashita,1 Akito Maeshima,1 Yoriaki Kaneko,1 Takashi Kuroiwa,1 Jeffrey B. Kopp,2 and Yoshihisa Nojima1

1Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan; and 2Kidney Disease Section, Kidney Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Submitted 7 April 2007 ; accepted in final form 17 July 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Conditional transgenic mice that express one of the human immunodeficiency virus (HIV)-1 accessory genes, vpr, selectively in podocytes using a podocin promoter and a tetracycline-inducible system develop renal injuries similar to those of patients with HIV-associated nephropathy (HIVAN). We have shown that a heminephrectomy accelerates podocyte injury, which is alleviated by angiotensin II (ANG II) type 1 receptor blocker (ARB). The current study further explores the role of ANG II in the genesis of HIVAN in this murine model. With ANG II infusion, heavy proteinuria was observed at 1 wk after the initiation of doxycycline administration to induce vpr expression in podocytes. Severe morphological and phenotypical changes in the podocytes were observed at 2 wk, together with extensive glomerulosclerosis. Norepinephrine infusion, instead of ANG II, increased the systemic blood pressure to the same level as that achieved using ANG II. However, albuminuria and glomerular injury were modest in norepinephrine-infused mice. Treatment with an ARB, olmesartan, almost completely inhibited glomerular injury. In contrast, lowering the blood pressure with a vasodilator, hydralazine, partially decreased albuminuria but did not produce any histological changes. ANG II infusion alone without doxycycline resulted in a lower level of albuminuria and minimal histological changes. These data demonstrate that excessive ANG II accelerates vpr-induced podocyte injury in a mouse model of HIVAN.

human immunodeficiency virus-associated nephropathy; proteinuria; glomerulosclerosis; angiotensin II type 1 receptor blocker; conditional transgenic mice

HUMAN IMMUNODEFICIENCY VIRUS (HIV)-associated nephropathy (HIVAN) is characterized by heavy proteinuria, rapidly progressive renal insufficiency, and distinct morphological changes in the kidney (2, 11, 20, 21, 28). The key histological features of HIVAN are segmental or global collapse of the glomerular capillary tuft, together with podocyte hypertrophy and hyperplasia as well as tubulointerstitial changes (2, 11, 20, 21, 28). Although the pathogenesis of HIVAN is not fully understood, the presence of the virus within renal cells, rather than immune dysregulation as a result of systemic HIV-1 infection, is considered to be important in the development of its characteristic histological changes (6, 23).

In human HIVAN, HIV-1 mRNA and DNA have been demonstrated in podocytes, parietal epithelial cells, renal tubular cells, and interstitial leukocytes (7, 32). In recently described transgenic mice, the selective expression of HIV-1 genes in podocytes was sufficient to evoke both glomerular and tubulointerstitial changes (16, 36, 37). Among the HIV-1 genes, including tat, rev, vif, vpu, vpr, and nef, only vpr and nef have been shown to result in the development of glomerular injury when expressed in podocytes alone (16, 37). Moreover, vpr and nef have a significant synergistic effect on podocyte injury. Although HIV-1 genes in podocytes are considered responsible for HIVAN, the mechanism responsible for podocyte damage leading to collapsing focal segmental glomerulosclerosis (FSGS) as a result of HIV-1 gene expression is not well understood.

Recently, our group (16) demonstrated that nephron reduction as a result of a heminephrectomy markedly accelerated vpr-induced podocyte injury and subsequent glomerular damage. We used dual transgenic mice (subsequently referred to as podocin/Vpr mice for simplicity) bearing a podocin/rtTA (reverse tetracycline transactivator) construct and a tetracycline-on (tetO)-vpr construct in which vpr expression is selectively induced in podocytes after the administration of doxycycline. We also demonstrated that angiotensin II (ANG II) type 1 receptor (AT1R) blockade almost completely inhibited the development and progression of renal injury in heminephrectomized-podocin/Vpr mice, suggesting that ANG II is involved in the exacerbation of podocyte injury (16). In the current study, to further examine the role of ANG II in vpr-induced podocyte injury, we continuously infused ANG II in podocin/Vpr mice instead of performing a heminephrectomy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Podocin/rtTA transgenic mice (FVB/N background) and tetO/Vpr mice were generated as previously described (16). The mice were then crossbred to generate dual transgenic mice bearing both the podocin/rtTA and tetO/Vpr transgenes. Following the administration of doxycycline, vpr was selectively expressed in the podocytes of podocin/Vpr mice. Seven- or eight-week-old bitransgenic mice, weighing 20–25 g, were used for the experiments. The animals were maintained under specific pathogen-free conditions. Mouse husbandry was carried out according to the protocols approved by the Animal Care Committee of Gunma University.

Experimental protocol. ANG II (1.44 mg·kg–1·day–1; Calbiochem, La Jolla, CA) was administered continuously using an osmotic pump (Alzet model 2004; Alza, Palo Alto, CA), which was implanted subcutaneously into the back of each podocin/Vpr mouse 2 days before the initiation of doxycycline administration. Doxycycline (Sigma-Aldrich, St. Louis, MO) was administered in drinking water (2 mg/ml) to induce vpr expression in the podocytes. Mice were also treated with olmesartan medoxomil (10 mg·kg–1·day–1; Sankyo, Tokyo, Japan) or hydralazine (15 mg·kg–1·day–1; Novartis Pharma, Tokyo, Japan) mixed with powdered food. Instead of ANG II, norepinephrine (2.8 mg·kg–1·day–1; Sankyo) was administered continuously via an osmotic pump. Tail-cuff plethysmography performed using a UR-1000 device (Ueda Avancer, Tokyo, Japan) was utilized to measure the systolic blood pressure in conscious mice.

Urinary and hematological analysis. Individual mice were placed in metabolic cages for 24-h urine collections. The urinary albumin concentration was determined using an ELISA kit (Albuwell M; Exocell, Philadelphia, PA). The serum albumin, total cholesterol, and urea nitrogen levels were assessed using a Hitachi 7180 autoanalyzer (Hitachi High-Technologies, Tokyo, Japan).

Histological analysis. Immunohistochemical staining was performed using paraffin-embedded kidney specimens as described previously. Briefly, 3-µm sections were deparaffinized, treated with hydrogen peroxide to block endogenous peroxidase, and microwaved to retrieve the antigens. The sections were then incubated overnight at 4°C with anti-Wilms tumor-1 (WT-1) antibody (Santa Cruz Biotechnology, Santa Cruz, CA), synaptopodin antibody (PROGEN, Heidelberg, Germany), or Ki-67 antibody (Lab Vision, Fremont, CA). After washing, the sections were incubated with a biotinylated secondary antibody (Vector Laboratories, Burlingame, CA) followed by the Vectastain ABC reagent (Vector Laboratories) and diaminobenzidine (Nichirei, Tokyo, Japan). Slides were counterstained using methyl green or periodic acid-Schiff reagent (PAS).

For immunofluorescence analysis, the kidneys were quick-frozen in liquid nitrogen and stored at –80°C. Sections (3 µm) were fixed with cold methanol-acetone (1:1) for 10 min at –20°C. The sections were then incubated with anti-nephrin antibody (PROGEN) followed by incubation with FITC-conjugated anti-guinea pig IgG antibody (Molecular Probes, Eugene, OR).

Scoring of glomerulosclerosis and podocyte markers. Glomerular injury was evaluated by grading sclerosis and hyalinosis in the glomeruli on PAS-stained sections, using a score of 0 to 4 for each glomerulus. The percentage of area with sclerosis or hyalinosis was scored for each glomerulus as follows: 0, no lesion; 1, <25%; 2, 25 to <50%; 3, 50 to 75%; 4, >5% of the glomerular tuft, respectively. More than 50 sequential glomeruli from each mouse were evaluated, and the average of glomerulosclerosis and hyalinosis scores was calculated.

To evaluate the podocyte markers, the number of WT-1- and Ki-67-positive cells in each glomerulus was examined. For Ki-67 staining, the number of positive cells was counted among those cells located within Bowman's space or on the glomerular basement membrane. Apparent parietal epithelial cells were excluded. More than 50 sequential glomeruli from each mouse were evaluated, and the average number of positive cells was calculated. For the evaluation of synaptopodin and nephrin expression, a semiquantitative grading system was used: 0, no stain; 1, weak staining; 2, intermediate staining; and 3, strong staining. The average staining score was calculated by counting more than 50 sequential glomeruli.

Statistical analyses. Data are means ± SD. Differences between experimental groups were evaluated using an ANOVA or Mann-Whitney test. Statistical significance was set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Continuous infusion of ANG II in podocin/Vpr mice. Podocin/Vpr mice express vpr, one of the HIV-1 accessory genes, selectively in podocytes after the administration of doxycycline. At 2–3 mo after the initiation of doxycycline administration, these mice exhibited renal injuries similar to those observed in patients with HIVAN (16). To determine the effect of ANG II in this mouse model of HIVAN, we continuously infused ANG II using a subcutaneously implanted osmotic pump (Fig. 1A). Podocin/Vpr mice showed trivial albuminuria (0.2 ± 0.1 mg/day) before the initiation of ANG II infusion. After the administration of both ANG II and doxycycline, massive albuminuria was observed on day 9 (34.0 ± 19.5 mg/day), further increasing on day 16 (73.1 ± 43.3 mg/day) (Fig. 1B). In contrast, podocin/Vpr mice treated with ANG II alone or doxycycline alone showed a slight increase in albuminuria on day 16 (1.8 ± 0.9 and 2.6 ± 1.9 mg/day, respectively) (Fig. 1B). On day 16, the systolic blood pressure was elevated in ANG II-treated mice both with or without doxycycline but not in mice treated with doxycycline alone (Fig. 1C). In ANG II-treated mice, the systolic blood pressure was slightly increased on day 2 (151 ± 10.2 mmHg), just before the administration of doxycycline, and more elevated on day 9 (171 ± 5.8 mmHg).


Figure 1
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  		Fig. 1. Effect of continuous angiotensin II (ANG II) infusion in podocin/Vpr mice. Experimental protocol (A), urinary albumin excretion (B), and systemic blood pressure (C) in mice with ANG II infusion plus doxycycline (Doxy) treatment (ANG II + Dox; n = 14), ANG II infusion alone (n = 8), or Doxy alone (n = 8). A marked elevation of urinary albumin excretion was observed in ANG II-infused, Doxy-treated mice. Increased systemic blood pressure was observed in ANG II-infused mice with or without Doxy treatment. *P < 0.01 vs. ANG II or Doxy alone. **P < 0.01 vs. Doxy alone; n.s., nonsignificant.

 
Effect of norepinephrine. To determine the effect of increased systolic blood pressure on albuminuria in podocin/Vpr mice, we next continuously infused the mice with norepinephrine, instead of ANG II (Fig. 2A). In mice treated with norepinephrine and doxycycline, increased albuminuria was observed on day 16 (4.1 ± 4.0 mg/day), but the level was much lower than that in mice treated with ANG II and doxycycline (Fig. 2B). The systolic blood pressure was similar in both groups on day 16 (Fig. 2C).


Figure 2
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  		Fig. 2. Effect of continuous norepinephrine (NE) infusion in podocin/Vpr mice. Experimental protocol (A), urinary albumin excretion (B), and systemic blood pressure (C) in mice with NE infusion (n = 12) and ANG II infusion (n = 14). Both groups received Doxy. Urinary albumin excretion was modest in NE-infused mice compared with ANG II-infused mice. No significant difference in increased systemic blood pressure was observed in either group. *P < 0.01 vs. ANG II.

 
Effect of antihypertensive drugs. We next determined the effect of antihypertensive drugs in ANG II-infused podocin/Vpr mice treated with doxycycline (Fig. 3A). We used olmesartan, an ARB, and hydralazine, an arteriolar vasodilator. Olmesartan almost completely inhibited albuminuria on day 16 (0.4 ± 0.2 mg/day). In contrast, the mice treated with hydralazine showed heavy albuminuria (34.4 ± 20.8 mg/day), although the amount of urinary albumin excretion was significantly lower than that in mice not treated with antihypertensive drugs (Fig. 3B). Systolic blood pressure was significantly lower in both olmesartan- and hydralazine-treated mice compared with mice that were not treated with antihypertensive drugs (Fig. 3C). No significant differences in systolic blood pressure were observed between olmesartan- and hydralazine-treated mice.


Figure 3
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  		Fig. 3. Effect of treatment with olmesartan (Olm) or hydralazine (Hyd) in podocin/Vpr mice. Experimental protocol (A), urinary albumin excretion (B), and systemic blood pressure (C) in mice treated with an ANG II type 1 receptor blocker (Olm; n = 11) or a vasodilator (Hyd; n = 10). All groups received continuous ANG II infusion and Doxy. Urinary albumin excretion was almost completely inhibited in the Olm-treated mice but not in the Hyd-treated mice. Systemic blood pressure was decreased in both groups compared with the mice with ANG II infusion without antihypertensive drugs. *P < 0.01 vs. ANG II without antihypertensive drugs.

 
Histological and serological analysis. We next examined the morphological changes in each group of mice by using light microscopy. As shown in Figs. 4, A and C, and fig. 5, ANG II-infused, doxycycline-treated mice showed extensive glomerulosclerosis and hyalinosis associated with morphological changes in the podocytes. Some podocytes became enlarged, and some became vacuolated. Occasionally, visceral epithelial cell hyperplasia and pseudocrescent formation were observed. These changes were almost completely prevented by the simultaneous administration of olmesartan (Figs. 4, B and D, and 5). In contrast, hydralazine could not protect against glomerulosclerosis in ANG II-infused, doxycycline-treated mice (Figs. 4E and 5). The glomerular lesions in norepinephrine-infused, doxycycline-treated mice were relatively weak (Figs. 4F and 5). Mice treated with ANG II alone or doxycycline alone also showed slight glomerular changes (Figs. 4, G and H, and 5). The serological data of each group of mice are shown in Table 1. Mice treated with both ANG II and doxycycline showed severe hypoalbuminemia, hypercholesterolemia, and elevated blood urea nitrogen levels. Olmesartan, but not hydralazine, inhibited these changes.


Figure 4
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  		Fig. 4. Renal histopathology of each group of mice. Renal sections obtained on day 16 after the initiation of the indicated therapy were stained with periodic acid-Schiff (PAS). Mice were treated with ANG II + Doxy (A and C), ANG II + Doxy plus Olm (B and D), ANG II + Doxy + Hyd (E), NE + Doxy (F), ANG II alone (G), or Doxy alone (H). ANG II-infused, Doxy-treated mice showed extensive glomerulosclerosis and hyalinosis associated with morphological changes in the podocytes. Treatment with Olm, but not Hyd, inhibited these changes. Magnification: A and B, x100; C–H, x400.

 

Figure 5
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  		Fig. 5. Glomerulosclerosis/hyalinosis score in each group of mice. Glomerulosclerosis and hyalinosis were assessed in each group of mice on day 16, as described in MATERIALS AND METHODS. Severe glomerulosclerosis and hyalinosis were observed in ANG II-infused, Doxy-treated mice. Treatment with Olm, but not Hyd, inhibited these changes.

 

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  		Table 1. Serological data for each group of mice

 
Phenotypic changes in podocytes. The dedifferentiation and dysregulation of podocytes have been observed in both humans and animal models of HIVAN (2, 3). Therefore, we examined the ANG II infusion-induced phenotypic changes in the podocytes of podocin/Vpr mice (Fig. 6 and Table 2). Expression of the podocyte markers WT-1, synaptopodin, and nephrin was depressed in ANG II-infused, doxycycline-treated mice, whereas the expression of Ki-67 was elevated. Significant changes in podocyte marker expression were also observed in hydralazine-treated mice. In contrast, olmesartan-treated mice showed sustained expression of WT-1, synaptopodin, and nephrin and minimal expression of Ki-67. Norepinephrine-infused, doxycycline-treated mice, ANG II-infused mice without doxycycline, and doxycycline-treated mice without ANG II showed only minor changes in these podocyte markers.


Figure 6
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  		Fig. 6. Immunostaining of podocyte makers and a proliferation marker. Renal sections from mice on day 0 and ANG II-infused, Doxy-treated mice on day 16 of treatment with or without Olm were immunohistochemically stained for Wilms tumor-1 (WT-1; A–C), synaptopodin (D–F), and Ki-67 (J–L). Sections were also stained using immunofluorescence for nephrin (G–I). ANG II-infused mice at day 16 showed decreased expression of WT-1, synaptopodin, and nephrin and increased expression of Ki-67 compared with the levels in mice on day 0. In contrast, Olm inhibited these changes. For Ki-67 staining, the number of positive cells was counted among those cells located within Bowman's space or on the glomerular basement membrane (K, arrows). Slides were counterstained with methyl green (A–F) or PAS (J–L). Magnification: x400.

 

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  		Table 2. Semiquantitative analysis for podocyte markers and a proliferation marker

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
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GRANTS
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The renin-angiotensin-aldosterone system plays a pivotal role in the regulation of renal vasomotor activity, the maintenance of optimal salt and water homeostasis, and the control of tissue growth in the kidney (4, 27). However, excessive ANG II can be involved in progressive kidney damage (4). By using animal models, the effect of continuous ANG II infusion on the kidney has been studied. ANG II infusion to normal rats elicits focal injury in small renal arterial vessels and focal tubulointerstitial injury. However, ANG II infusion alone is not enough to induce severe morphological changes in the glomerulus, although it induces mild proteinuria (18, 26). In the Habu venom toxin-induced nephritis, a model of mesangioproliferative glomerulonephritis, ANG II infusion markedly accelerates tubulointerstitial nephritis, together with heavy proteinuria and glomerulosclerosis (14). In the anti-Thy 1.1 nephritis, the other model of mesangioproliferative glomerulonephritis, the effect of ANG II is controversial. Continuous subcutaneous ANG II infusion ameliorates the early phase of mesangioproliferative glomerulonephritis (31, 34), whereas local delivery of ANG II using a type 1 collagen sponge exaggerates proteinuria in a rat progressive glomerulonephritis model, in which anti-Thy-1 antibody is injected, followed by a heminephrectomy (25). In the current study, we used podocin/Vpr mice, in which the expression of an HIV-1 gene, vpr, is induced selectively in podocytes after doxycycline administration, to examine the effect of continuous ANG II infusion on podocyte injury. We demonstrated that ANG II infusion strikingly accelerates proteinuria and glomerulosclerosis in the setting of vpr expression in podocytes.

ANG II-infused podocin/Vpr mice showed accelerated morphological and phenotypic changes in their podocytes. The extensive loss of the podocyte marker WT-1 and its maturity markers, synaptopodin and nephrin, was observed, together with an increased expression of Ki-67, a marker for cell cycle activation. Thus ANG II infusion enhanced the dysregulation and dedifferentiation of podocytes, leading to proteinuria and glomerulosclerosis. To our knowledge, this is the first report to demonstrate that ANG II infusion enhances obvious morphological and phenotypical changes in podocytes. How might ANG II affect podocyte injury? The adverse effects of ANG II on the progression of renal injury are thought to be associated with systemic and glomerular capillary hypertension and the profibrotic effects of ANG II (4). Our data show that the effect of ANG II on vpr-induced podocyte damage was independent of systemic blood pressure. Treatment with ARB, but not hydralazine, almost completely inhibited these changes. Norepinephrine infusion, instead of ANG II, also increased the systemic blood pressure to the same level as that induced by ANG II. However, norepinephrine did not induce heavy proteinuria or extensive histological changes.

We propose that two mechanisms may be involved in the acceleration of podocyte injury by ANG II. First, an increased intraglomerular capillary pressure may affect the podocytes. ANG II is a potent vasoconstrictor and is known to increase systemic blood pressure. In the glomeruli, ANG II is considered to increase glomerular capillary pressure by narrowing the efferent arterioles more than the afferent arterioles (12, 35). Thus increased glomerular capillary pressure may enhance morphological and phenotypical changes in the podocytes and lead to heavy proteinuria and glomerulosclerosis. Second, ANG II itself may directly affect the podocytes. In cultured podocytes, ANG II is reported to affect membrane voltage and conductance properties (15), the expression of heparan sulfate proteoglycans (5), the production of {alpha}3 (IV) collagen (9), and the cytoskeleton redistribution, including the shedding of nephrin (13, 24). The infusion of ANG II in isolated rat kidneys causes an impairment of the glomerular barrier, leading to the enhanced filtration of larger molecules and increased protein excretion (22). Transgenic rats expressing AT1R in podocytes develop albuminuria and structural podocyte damage that progresses to FSGS (17). Since we infused ANG II, not only AT1R but also ANG II type 2 receptor (AT2R) seems to be involved. However, our results show that AT1R blockade almost completely suppressed ANG II-induced podocyte injury, so we think that the aggravation of podocyte injury by ANG II in our model is largely dependent on AT1R, and the role of AT2R should be minimal. For now, we do not know whether increased intraglomerular capillary pressure or direct stimulation of ANG II is involved in the acceleration of vpr-induced podocyte injury. The precise mechanism of injury needs to be determined in the future.

Clinically, HIVAN is an important cause of end-stage renal disease (ESRD) in patients of African descent (10, 29). In early studies conducted in the pre-AZT (zidovudine) era, the median time to dialysis was 3–4 mo (8, 10, 28). By introducing antiviral therapy, especially the use of highly active antiretroviral therapy (HAART), the progression to ESRD has slowed (1, 30). In addition to antiviral therapy, the beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) on HIVAN progression also has been reported (19, 33). The use of ACEi has been associated with enhanced renal survival in retrospective studies of patients with HIVAN, suggesting that ANG II is also involved in the exacerbation of renal injury in patients with HIVAN. Our data support the usage of ACEi or ARB for the treatment of HIVAN, especially for protection against the development and progression of podocyte injury resulting from the increased activation of the renin-angiotensin system.

In conclusion, we have shown that continuous ANG II infusion dramatically accelerated podocyte injury in a mouse model of HIVAN. Podocytes showed severe morphological and phenotypical changes under selective vpr expression and ANG II infusion. The effect of ANG II was independent of systemic blood pressure and was almost completely inhibited by AT1R blockade. These data demonstrate that excessive ANG II is critically involved in the development and progression of vpr-induced podocyte injury and subsequent glomerular damage.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to K. Hiromura) and a Grant-in Aid from Gunma University (to K. Hiromura).


   ACKNOWLEDGMENTS
 
Olmesartan medoxomil was kindly supplied by Sankyo (Tokyo, Japan). We thank Rumiko Koitabashi for help in the preparation of kidney biopsy sections.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. Hiromura, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan (e-mail: hiromura{at}med.gunma-u.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Atta MG, Gallant JE, Rahman MH, Nagajothi N, Racusen LC, Scheel PJ, Fine DM. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant 21: 2809–2813, 2006.[Abstract/Free Full Text]
  2. Barisoni L, Bruggeman LA, Mundel P, D'Agati VD, Klotman PE. HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy. Kidney Int 58: 173–181, 2000.[CrossRef][Web of Science][Medline]
  3. Barisoni L, Kriz W, Mundel P, D'Agati V. The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 10: 51–61, 1999.[Abstract/Free Full Text]
  4. Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med 116: 263–272, 2004.[CrossRef][Web of Science][Medline]
  5. Brinkkoetter PT, Holtgrefe S, van der Woude FJ, Yard BA. Angiotensin II type 1-receptor mediated changes in heparan sulfate proteoglycans in human SV40 transformed podocytes. J Am Soc Nephrol 15: 33–40, 2004.[Abstract/Free Full Text]
  6. Bruggeman LA, Dikman S, Meng C, Quaggin SE, Coffman TM, Klotman PE. Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J Clin Invest 100: 84–92, 1997.[Web of Science][Medline]
  7. Bruggeman LA, Ross MD, Tanji N, Cara A, Dikman S, Gordon RE, Burns GC, D'Agati VD, Winston JA, Klotman ME, Klotman PE. Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol 11: 2079–2087, 2000.[Abstract/Free Full Text]
  8. Carbone L, D'Agati V, Cheng JT, Appel GB. Course and prognosis of human immunodeficiency virus-associated nephropathy. Am J Med 87: 389–395, 1989.[Web of Science][Medline]
  9. Chen S, Lee JS, Iglesias-de la Cruz MC, Wang A, Izquierdo-Lahuerta A, Gandhi NK, Danesh FR, Wolf G, Ziyadeh FN. Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy. Nephrol Dial Transplant 20: 1320–1328, 2005.[Abstract/Free Full Text]
  10. D'Agati V, Appel GB. HIV infection and the kidney. J Am Soc Nephrol 8: 138–152, 1997.[Abstract]
  11. D'Agati V, Appel GB. Renal pathology of human immunodeficiency virus infection. Semin Nephrol 18: 406–421, 1998.[Web of Science][Medline]
  12. Denton KM, Fennessy PA, Alcorn D, Anderson WP. Morphometric analysis of the actions of angiotensin II on renal arterioles and glomeruli. Am J Physiol Renal Fluid Electrolyte Physiol 262: F367–F372, 1992.[Abstract/Free Full Text]
  13. Doublier S, Salvidio G, Lupia E, Ruotsalainen V, Verzola D, Deferrari G, Camussi G. Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes 52: 1023–1030, 2003.[Abstract/Free Full Text]
  14. Faulkner JL, Szcykalski LM, Springer F, Barnes JL. Origin of interstitial fibroblasts in an accelerated model of angiotensin II-induced renal fibrosis. Am J Pathol 167: 1193–1205, 2005.[Abstract/Free Full Text]
  15. Gloy J, Henger A, Fischer KG, Nitschke R, Mundel P, Bleich M, Schollmeyer P, Greger R, Pavenstadt H. Angiotensin II depolarizes podocytes in the intact glomerulus of the Rat. J Clin Invest 99: 2772–2781, 1997.[Web of Science][Medline]
  16. Hiramatsu N, Hiromura K, Shigehara T, Kuroiwa T, Ideura H, Sakurai N, Takeuchi S, Tomioka M, Ikeuchi H, Kaneko Y, Ueki K, Kopp JB, Nojima Y. Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model. J Am Soc Nephrol 18: 515–527, 2007.[Abstract/Free Full Text]
  17. Hoffmann S, Podlich D, Hahnel B, Kriz W, Gretz N. Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol 15: 1475–1487, 2004.[Abstract/Free Full Text]
  18. Johnson RJ, Alpers CE, Yoshimura A, Lombardi D, Pritzl P, Floege J, Schwartz SM. Renal injury from angiotensin II-mediated hypertension. Hypertension 19: 464–474, 1992.[Abstract/Free Full Text]
  19. Kimmel PL, Mishkin GJ, Umana WO. Captopril and renal survival in patients with human immunodeficiency virus nephropathy. Am J Kidney Dis 28: 202–208, 1996.[Web of Science][Medline]
  20. Kopp JB, Winkler C. HIV-associated nephropathy in African Americans. Kidney Int Suppl: S43–S49, 2003.
  21. Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 67: 404–419, 2005.[CrossRef][Web of Science][Medline]
  22. Lapinski R, Perico N, Remuzzi A, Sangalli F, Benigni A, Remuzzi G. Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney. J Am Soc Nephrol 7: 653–660, 1996.[Abstract]
  23. Lu TC, Ross M. HIV-associated nephropathy: a brief review. Mt Sinai J Med 72: 193–199, 2005.[Medline]
  24. Macconi D, Abbate M, Morigi M, Angioletti S, Mister M, Buelli S, Bonomelli M, Mundel P, Endlich K, Remuzzi A, Remuzzi G. Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target for renoprotective intervention. Am J Pathol 168: 1073–1085, 2006.[Abstract/Free Full Text]
  25. Mahmood J, Khan F, Okada S, Kumagai N, Morioka T, Oite T. Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis. Kidney Int 70: 1591–1598, 2006.[CrossRef][Web of Science][Medline]
  26. Mirani M, Elenkov I, Volpi S, Hiroi N, Chrousos GP, Kino T. HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action: potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection. J Immunol 169: 6361–6368, 2002.[Abstract/Free Full Text]
  27. Niimura F, Labosky PA, Kakuchi J, Okubo S, Yoshida H, Oikawa T, Ichiki T, Naftilan AJ, Fogo A, Inagami T, Hogan BL, Ichikawa I. Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest 96: 2947–2954, 1995.[Web of Science][Medline]
  28. Rao TK, Filippone EJ, Nicastri AD, Landesman SH, Frank E, Chen CK, Friedman EA. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 310: 669–673, 1984.[Abstract]
  29. Ross MJ, Klotman PE. Recent progress in HIV-associated nephropathy. J Am Soc Nephrol 13: 2997–3004, 2002.[Free Full Text]
  30. Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R, Fields TA, Svetkey LP, Flanagan KH, Klotman PE, Winston JA. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int 66: 1145–1152, 2004.[CrossRef][Web of Science][Medline]
  31. Takazawa Y, Maeshima Y, Kitayama H, Yamamoto Y, Kawachi H, Shimizu F, Matsui H, Sugiyama H, Yamasaki Y, Makino H. Infusion of angiotensin II reduces loss of glomerular capillary area in the early phase of anti-Thy-1.1 nephritis possibly via regulating angiogenesis-associated factors. Kidney Int 68: 704–722, 2005.[CrossRef][Web of Science][Medline]
  32. Tanji N, Ross MD, Tanji K, Bruggeman LA, Markowitz GS, Klotman PE, D'Agati VD. Detection and localization of HIV-1 DNA in renal tissues by in situ polymerase chain reaction. Histol Histopathol 21: 393–401, 2006.[Web of Science][Medline]
  33. Wei A, Burns GC, Williams BA, Mohammed NB, Visintainer P, Sivak SL. Long-term renal survival in HIV-associated nephropathy with angiotensin-converting enzyme inhibition. Kidney Int 64: 1462–1471, 2003.[CrossRef][Web of Science][Medline]
  34. Wenzel UO, Thaiss F, Helmchen U, Stahl RA, Wolf G. Angiotensin II infusion ameliorates the early phase of a mesangioproliferative glomerulonephritis. Kidney Int 61: 1020–1029, 2002.[CrossRef][Web of Science][Medline]
  35. Yuan BH, Robinette JB, Conger JD. Effect of angiotensin II and norepinephrine on isolated rat afferent and efferent arterioles. Am J Physiol Renal Fluid Electrolyte Physiol 258: F741–F750, 1990.[Abstract/Free Full Text]
  36. Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, Matsusaka T. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int 68: 1048–1060, 2005.[CrossRef][Web of Science][Medline]
  37. Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, Jolicoeur P, Fogo AB, Ichikawa I. HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol 17: 2832–2843, 2006.[Abstract/Free Full Text]



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