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Pathophysiology of Renal Disease and Progression |
* Institute of Medical Sciences and Division of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan; Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan; and Service de Nephrologie, Universite Catholique de Louvain, Brussels, Belgium
Address correspondence to: Dr. Toshio Miyata, Institute of Medical Sciences and Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Phone: +81-463-93-1936; Fax: +81-463-93-1938; E-mail: t-miyata{at}is.icc.u-tokai.ac.jp
Received for publication May 18, 2005. Accepted for publication September 8, 2005.
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Abstract |
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blockers (BB) on various mediators were compared: Formation of pentosidine (an advanced glycation end product), hydroxyl radical-induced formation of o-tyrosine, and transition metals–induced oxidation of ascorbic acid (the Fenton reaction). All of the six tested ARB but neither the six CCB nor the nine BB inhibited pentosidine formation. ARB, as well as BB but not CCB, inhibited hydroxyl radicals–mediated o-tyrosine formation. ARB but neither BB nor CCB inhibited efficiently transition metals–catalyzed oxidation of ascorbic acid. Second, the in vivo consequences for the kidney of these various in vitro effects were evaluated. Hypertensive, type 2 diabetic rats with nephropathy, SHR/NDmcr-cp, were given for 20 wk either olmesartan (ARB) or nifedipine (CCB), or atenolol (BB). Despite similar BP reduction, only ARB significantly reduced proteinuria and prevented glomerular and tubulointerstitial damage (mesangial activation, podocyte injury, tubulointerstitial injury, and inflammatory cell infiltration). It is interesting that only ARB prevented abnormal iron deposition in the interstitium, corrected chronic hypoxia, reduced expressions of heme oxygenase and p47phox (a subunit of NADPHoxidase), and inhibited pentosidine formation (which correlates well with proteinuria). These observations confirm unique renoprotective properties of ARB, independent of BP lowering but related to decreased oxidative stress (hydroxyl radicals scavenging and inhibition of the Fenton reaction), correction of chronic hypoxia, and inhibition of advanced glycation end product formation and of abnormal iron deposition. These benefits of ARB may contribute to the renoprotection observed beyond BP lowering. |
Introduction |
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The nature of the renoprotection provided by some antihypertensive agents independent of BP lowering and inhibition of the RAS thus has become a topic of major interest. We previously demonstrated in vitro that ARB and ACEI but not nifedipine inhibit, in diabetic or uremic serum, the formation of advanced glycation end products (AGE) (11), previously implicated in the pathology of diabetic complications and atherosclerosis (12–16). The AGE inhibitory effect of ARB, unlike that of ACEI, is linked to a common core structure, 5-(4' methylbiphenyl-2-yl)-1H-tetrazol. It thus is a class effect (11). By contrast, ACEI have no common core structure and it is not conclusive whether the AGE inhibitory effect of ACEI is a class effect.
We now extend this in vitro approach to several other renoprotective mechanisms and compare the effects of ARB, CCB, and blockers (BB). In this model, the effects of the various antihypertensive drugs are independent of BP lowering or RAS modifications. Clearly, only ARB combined unique in vitro properties, possibly involved in renoprotection (e.g., hydroxyl radicals scavenging, inhibition of AGE formation and of the Fenton reaction by transition metal chelation).
The in vivo relevance of these in vitro results is confirmed, at least in part, in a hypertensive, type 2 diabetic rat model with nephropathy, SHR/NDmcr-cp. Despite similar BP-lowering effects, only an ARB significantly reduces proteinuria and prevents glomerular and tubulointerstitial damage (mesangial activation, podocyte injury, tubulointerstitial injury, and inflammatory cell infiltration). These benefits coincide with reduced AGE formation. Of great interest, they are concomitant with the prevention of abnormal iron deposition and of expressions of heme oxygenase-1 (HO-1) and p47phox (a subunit of NADPHoxidase) and with the correction of chronic hypoxia in the tubulointerstitium.
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Materials and Methods |
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In Vitro Studies
Pentosidine Measurement by HPLC.
Fresh heparinized plasma samples were obtained after informed consent from hemodialysis patients before the dialysis session. Pooled plasma (n = 4) was incubated with the tested reagents (final concentration of 0.8, 2.0, and 5.0 mM) for 1 wk under air at 37°C. The pentosidine content was analyzed on a reverse-phase HPLC as described previously (17). Synthetic pentosidine was used as a standard.
Inhibition of Hydroxyl Radical–Mediated Phenylalanine Modification.
Phenylalanine (1 mM) and the tested compound (final concentration of 0.1, 0.5, and 2.5 mM) were dissolved in 200 mM of phosphate buffer (pH 7.4) and incubated at room temperature for 4 h with H2O2 (5 mM) in the presence of 0.1 mM CuSO4 as a catalyst. After the metal-catalyzed oxidation reactions were quenched by addition of 1 mM diethylenetriamine pentaacetic acid (DTPA) and 260 units of catalase, o-tyrosine was measured by reverse-phase HPLC using a C18 reverse-phase column with fluorescence detector at an excitation of 275 nm, emission 305 nm (18). The very low water solubility of some antihypertensive agents prevented their evaluation in this assay.
Metal Chelating Activity.
The chelating activity of the tested compounds for transition metal ions was measured by the method described previously (11).
In Vivo Studies
Animals.
The previously used (19) male subline of spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp) was investigated. Rats, aged 13 wk, were randomly divided into four groups and allocated to various regimens for an additional 20 wk as follows: 10 rats on vehicle; 10 rats on an ARB, olmesartan (5 mg/kg per d); 10 rats on a CCB, nifedipine (45 mg/kg per d); and 10 rats on a BB, atenolol (20 mg/kg per d). Ten control WKY rats were on vehicle. Carboxymethylcellulose that contained the antihypertensive agent was given orally to rats by gavage. Taking into account their plasma half-lives, olmesartan and atenolol were given once and nifedipine was three times a day. The protocol was in accordance with the Animal Experimentation Guidelines of Tokai University.
BP, Urine Collection, and Blood Sampling.
Systolic BP was determined in conscious rats by the tail-cuff method at the beginning of the study and every 2 wk thereafter until the rats were killed at 33 wk. At the end of the study, each rat was weighed and placed in a metabolic cage for a 24-h urine collection. Blood samples were obtained before death.
Biochemical Measurements in Blood and Urine.
Total cholesterol, triglyceride, urea nitrogen (BUN), and albumin concentrations were determined in plasma, and protein concentrations were determined in urine with an automatic analyzer (Synchron CX7; Beckman Coulter Inc., Fullerton, CA). Plasma insulin was measured with commercially available kits (Morinaga Biochemistry Lab, Tokyo, Japan). Hemoglobin A1c was measured using the immunoassay technique by DCA2000 (Bayer HealthCare, Tarrytown, NY).
Renal Pentosidine Content.
Kidney tissue (100 mg) was minced, rinsed with 10% TCA, dried under vacuum, and acid hydrolyzed. Its pentosidine content then was quantified as described above.
Morphologic Analysis
Coronal sections of renal tissue (3 to 4 µm thick) were stained with periodic acid-Schiff and examined by light microscopy in a blinded manner for morphologic analysis. Glomerular sclerosis was semiquantitatively evaluated according to a previous paper (19). The severity of glomerular sclerosis was graded according to the percentage of sclerotic area expressed as a percentage of total area (0, no lesions; 1+, 1 to 25%; 2+, 25 to 50%; 3+, 50 to 75%; 4+, 75 to 100%). An overall glomerular sclerosis score per animal was obtained by multiplying each severity score (0 to 4+) with the percentage of glomeruli that displayed the same degree of injury and summing these scores.
Immunohistochemistry
Desmin, a marker of podocyte injury; 
-smooth muscle actin, a marker of mesangial injury; vimentin, a marker of tubulointerstitial injury; and monocytes/macrophages infiltration were detected in tissue sections (4 µm) of kidneys that were fixed with methyl Carnoy’s. For HO-1, tissue samples were fixed with formalin. The sections first were incubated with the appropriate mouse mAb (desmin by D33, 4.6 µg/ml [Dako, Carpinteria, CA]; vimentin by V9, 7.2 µg/ml [Dako]; -smooth muscle actin by asm-1, 0.5 µg/ml [Neomarkers, Fremont, CA]; monocytes/macrophages by ED-1, 5 µg/ml [Serotec, Oxford, UK]), or rabbit polyclonal antibody to HO-1 (1: 200 dilution; StressGen, Victoria, BC, Canada). Subsequently, the sections were incubated with biotinylated horse anti-mouse IgG polyclonal antibody (Vector Laboratories Inc., Burlingame, CA; 1:400 dilution). Development was performed with peroxidase-conjugated avidin (Vector Laboratories Inc.) and 3,3'-diaminobenzidine tetrahydrochloride (Wako, Osaka, Japan).
For semiquantitative analysis, desmin staining was graded as follows: 0, no staining; 1+, 1 to 25% of the glomerular tufts positive; 2+, 25 to 50%; 3+, 50 to 75%; 4+, 75 to 100%. Fifty glomeruli were selected randomly in each animal, and an overall score per animal was obtained by multiplying each score (0 to 4+) with the percentage of glomeruli that displayed the same degree of injury and summing these scores. Vimentin-positive tubules were counted in 10 randomly selected cortical fields with a x10 objective. ED-1–positive cells that infiltrated the tubulointerstitium were counted in 20 randomly selected cortical fields with x20 objective.
Detection of Tissue Iron Deposition
Prussian blue staining was used to detect iron deposition (20). After deparaffinization, the sections (4 µm) of formalin-fixed tissues were washed in deionized water and stained with 2% HCl/potassium ferrocyanide solution for 10 to 20 min. The sections were counterstained with nuclear fast red.
Detection of Hypoxia
Hypoxia was detected in renal tissues of SHR/NDmcr-cp rats that were treated with olmesartan. A hypoxic probe, pimonidazole (60 mg/kg; Chemicon, Temecula, CA), was injected intravenously 2 h before the rats were killed (21). Renal tissues then were obtained, fixed in formalin, and paraffin embedded. Accumulation of pimonidazole in hypoxic cells was detected by a specific mAb, Hypoxyprobe-1 Mab 1 (Hypoxyprobe-1 kit for the detection of tissue hypoxia; Chemicon) according to the method recommended by the manufacturer.
Statistical Analyses
All data are expressed as the mean ± SEM. The differences among the four SHR/NDmcr-cp groups were assessed by one-way ANOVA. Multiple comparisons were performed between the vehicle group and the other three groups of SHR/NDmcr-cp by Dunnett t test. The SHR/NDmcr-cp vehicle group was compared with the WKY group by Student t test. For histologic data, the differences among the four SHR/NDmcr-cp groups were assessed by Kruskal-Wallis test. Multiple comparisons were performed between the vehicle group and the other three groups of SHR/NDmcr-cp by Mann-Whitney U test. Differences between vehicle and WKY were assessed by Mann-Whitney U test. All calculations relied on SAS software (SAS Institute, Cary, NC). Values are considered significant at P < 0.05.
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Results |
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In comparison with control WKY rats, SHR/NDmcr-cp rats were hypertensive at the end of the study (P < 0.001). The three antihypertensive agents significantly decrease systolic BP to control WKY levels throughout the experiment (Table 4). No significant difference was observed in the level of BP achieved with each drug, although animals that were given olmesartan tended to have slightly lower levels.
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AGE Inhibition.
The renal pentosidine content of the kidneys, expressed as pmol/mg protein (Table 4), was significantly (P < 0.001) higher in the SHR/NDmcr-cp vehicle group than in the WKY group. Olmesartan but not nifedipine or atenolol returned renal pentosidine content toward control level (P < 0.001). The renal pentosidine content (pmol/mg of tissue proteins) observed in all SHR/NDmcr-cp rats, whether given vehicle or any of the three antihypertensive agents, was significantly correlated (P < 0.01) with proteinuria (mg/d; n = 40, R2 = 0.3522, y = 0.0004x + 0.0530).
Renal Histology and Immunohistochemistry
On light microscopy, segmental sclerosis with attachment of the capillary tuft to the Bowman’s capsule (Figure 1A) and tubulointerstitial injury (tubular dilation, atrophy of tubular epithelial cells, fibrosis, and infiltration of inflammatory cells) were observed in SHR/NDmcr-cp rats that were given vehicle. Glomerular (Table 5) and tubulointerstitial injury (data not shown) was markedly ameliorated (P < 0.05) but not fully corrected in SHR/NDmcr-cp rats that were given olmesartan. No effect was noted in rats that were given nifedipine or atenolol.
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-Smooth muscle actin (Figure 1D), a marker of mesangial injury and activation (25), was expressed in three to five glomeruli per section in SHR/NDmcr-cp rats that were given vehicle, nifedipine, or atenolol. These changes were improved by olmesartan: No -smooth muscle actin–positive mesangial cells were detected in these animals. Macrophage infiltration, assessed with ED-1 (Figure 1E), was present in the tubulointerstitium of SHR/NDmcr-cp rats that were given vehicle, nifedipine, or atenolol but markedly diminished in rats that were given olmesartan. Semiquantitative analysis of desmin staining as well as the count of vimentin-positive tubules and ED-1 positive infiltrating cells confirmed these observations (Table 6).
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Discussion |
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ARB also inhibit oxidative metabolism as now demonstrated directly by their ability to block o-tyrosine formation by hydroxyl radicals. This effect is shared to a minor extend by BB but is absent in CCB. Previous in vitro data (11) already hinted that ARB reduce oxidative metabolism as olmesartan, an ARB, scavenges carbon-centered and hydroxyl-radicals and decreases, accordingly, the formation of dicarbonyls such as glyoxal or methylglyoxal. Taken together, these data establish conclusively a direct antioxidant effect of ARB.
All ARB also share the chelating activity for transition metals involved in the Fenton reaction generating hydroxyl radicals. Neither the CCB nor the BB have this effect.
The in vivo relevance of these three effects (inhibition of advanced glycation and oxidative metabolism and the chelation of transition metals) as well as their respective contributions to renoprotection was evaluated further in a hypertensive type 2 diabetic rat model with nephropathy, the SHR/NDmcr-cp strain (29). In this model, rats develop obesity, hyperglycemia with hyperinsulinemia, and hyperlipidemia. Renal involvement is expressed by proteinuria and pathologic lesions of the glomeruli and as we now demonstrate the tubulointerstitium (19). Striking, olmesartan, an ARB, but neither nifedipine, a CCB, nor atenolol, a BB, reduces proteinuria and kidney lesions. The effect on BP, body weight, glucose levels, and lipid disorders is similar for ARB, CCB, and BB and thus does not mediate ARB-induced renoprotection. By contrast, the in vitro demonstrated characteristics of ARB have their in vivo counterpart in the diabetic kidneys.
Inhibition of advanced glycation translates into a marked reduction of the renal pentosidine content observed only in olmesartan-treated rats. The pathologic relevance of this phenomenon is illustrated by the tight correlation observed between proteinuria and renal pentosidine content when all results of the experimental groups are combined. This already published relationship (19) remains highly significant after inclusion of the data of the nifedipine-treated animals.
The in vivo impact of ARB on oxidative stress and transition metal chelation within the diabetic kidney remains to be ascertained. It is difficult to measure directly the degree of the Fenton reaction and the generation of hydroxyl radicals within renal tissues. The iron deposits observed within diabetic kidneys and their disappearance only after olmesartan treatment is of interest. Iron deposition has harmful consequences for the kidney (30–32). The extent of iron accumulation in proximal tubular cells, both in human chronic renal disease (33) and in the rat hemosiderosis model (34), correlates with proteinuria but not with GFR. Conversely, the iron chelator, desferrioxamine, prevents iron deposition in tubular cells of rats that are given angiotensin II and reduces proteinuria (35). Iron staining therefore may provide investigators with an easy tool to ascertain in vivo the renoprotective effects of various treatments. The exact relationship among in vitro metal chelation, the in vivo reduction of iron deposits, and the direct inhibition of oxidative metabolism is still to be investigated.
Iron deposition might reflect an increased activity of the RAS. Indeed, angiotensin II infusion provokes marked iron deposition in the rat kidney (35). However, an exclusive role of angiotensin is unlikely as hydralazine, a RAS-independent antihypertensive agent, is also able to reduce iron deposition in rats (35). Noteworthy, iron deposition in the tubulointerstitium parallels the infiltration of inflammatory cells. Apoptotic degradation of inflammatory cells might release intracellular iron into the interstitial space. The simultaneous correction of abnormal iron deposition, tubulointerstitial fibrosis, and inflammatory cell infiltration by ARB renders moot the identification of a primary phenomenon.
Indirect evidence for in vivo ARB protection against oxidative stress accrues also from our observations on the antioxidative renoprotective genes in the kidney. On immunohistochemistry, expression of HO-1, one of the renal antioxidative proteins, was upregulated in diabetic rat kidney but returned to normal levels by olmesartan. Similarly, the mRNA of p47phox, a subunit of NADPH oxidase, was upregulated in the rat diabetic kidney but returned to normal by ARB. HO-1 expression is known to be enhanced by the hypoxia-inducible factor (36) as well as by abnormal iron deposition (37) and angiotensin II infusion (38). It protects against iron-induced tissue injury by generating the antioxidants biliverdin and bilirubin (39) or by modulating the levels of intracellular iron (40). Altogether, these data might reflect an ARB-induced reduction of oxidative stress possibly through the prevention of chronic hypoxia, abnormal iron deposition, and/or RAS activation.
Our results not only identify the consequences for the diabetic kidney of the in vitro demonstrated effects of ARB but also delineate a number of other features associated with ARB-induced renoprotection. Olmesartan but neither nifedipine nor atenolol reverses several abnormalities that are present in rat diabetic nephropathy: It decreases glomerular sclerosis, lowers the stimulation of mesangial cells witnessed by -smooth actin expression, preserves podocytes as illustrated by the prevention of desmin expression, protects against interstitial fibrosis as shown by the absence of vimentin, and inhibits the infiltration of macrophages stained by ED-1 antibody.
In this study, we also demonstrate the presence of hypoxia in diabetic kidneys and its reversal by ARB but not by CCB and BB. Chronic hypoxia plays a crucial role in the progression of renal disease (41–43). Its presence has been documented early in the evolution of diabetic kidneys (42). Its causes are multifactorial. They include constriction of efferent arterioles by angiotensin II with an attendant decrease in peritubular capillary flow. Norman’s group (44) and ours (45) have shown independently that RAS blockade improves tubulointerstitial hypoxia.
Olmesartan is also the only antihypertensive drug that is able to reduce the infiltration of the interstitium by inflammatory cells. This benefit might result from an amelioration of hypoxia, which is known to induce tubulointerstitial injury and an attendant infiltration by inflammatory cells. Alternatively, olmesartan might correct an imbalance between helper T cell subsets followed by an ameliorated tubulointerstitial inflammation, as observed after angiotensin II infusion in another hypertensive kidney injury model (46). Further discussion of the cytokine balance in our model of diabetic nephropathy is beyond our scope.
The phenomena associated with diabetic nephropathy seem to be heterogeneous. They are tentatively integrated in a hypothetical scheme depicted in Figure 5, suggesting an interaction among oxidative stress, AGE formation, chronic hypoxia, iron deposition, and inflammatory cell infiltration. Abnormal iron deposition accelerates the Fenton reaction and eventual hydroxyl radical generation (22), which in turn increases oxidative stress and AGE formation. The last further interacts with the receptor for AGE with an attendant release of reactive oxygen species and eventual chemotactic attraction of macrophages (47,48). Chronic hypoxia in the tubulointerstitial tissue transforms tubular cells into myofibroblasts and accelerates tissue fibrosis (49), which is further exacerbated by concomitant inflammatory cells infiltration, oxidative matrix protein damage, and AGE modification. Whatever its truth, this hypothesis provides a useful frame for further investigations.
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Whatever the sequential mechanisms of diabetic renal injury, our observations confirm that, among several antihypertensive agents, ARB have unique properties that rely certainly on signs of decreased oxidative stress (hydroxyl radicals scavenging and inhibition of the Fenton reaction); correction of chronic hypoxia; and inhibition of AGE formation, of abnormal iron deposition, and of inflammatory cell infiltration. They confirm clinical evidence that BB have no such effect (5) and support the studies that deny an additional renoprotective role to CCB beyond BP lowering. Finally, our results allow some speculations on the genesis of diabetic nephropathy and identify targets of interest for its prevention. Exploration of the interrelationships among RAS activation, oxidative stress, chronic hypoxia, iron deposition, inflammatory cell infiltration, and diabetic renal injury warrants further studies.
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Acknowledgments |
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Footnotes |
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