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Biomedical subjects

I Ichikawa

Publications and source records attributed to I Ichikawa.

At least 19 recordsLinked to original sources
PubMed1995

Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor.

There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.

Angiotensin II↗
PubMed1995

Strategic locus for the activation of the superoxide dismutase gene in the nephron.

Upon exposure to a transient ischemia, the distal tubule of the kidney often escapes the severe damage which afflicts the proximal tubule. To ascertain whether this feature of the distal tubule is attributable to its intrinsic cellular properties, we focused on two pairs of unique tubule segments; distal versus proximal convoluted tubules in the superficial cortex and distal versus proximal straight tubules in the outer stripe of the outer medulla. These tubules were chosen because, firstly, they can be identified by morphology and immunostaining, and secondly, each pair has the same anatomical relationship to the circulation. Detailed morphometric analyses were performed six hours following unilateral transient ischemia in adult rats to semiquantitate the local tissue damage in these specific nephron segments. The architecture of the distal convoluted and straight tubules was remarkably well preserved, contrasting to the moderate to extensive necrotic changes seen in the proximal tubules. In search of the potential intrinsic cellular mechanism that underlies the observed difference, we examined the segmental distribution along the nephron of manganese superoxide dismutase gene transcripts by in situ hybridization. This antioxidant enzyme gene was expressed primarily in the distal tubules with contrastingly low levels of expression in the proximal tubules. Moreover, following ischemia-reperfusion, this distal tubule-dominant pattern was further accentuated immediately following reperfusion. The study indicates that the marked difference between the proximal and distal tubules in their susceptibility to injury in vivo is attributable to their intrinsic cellular properties, which include the local level of antioxidants.

Animals↗
PubMed1995

Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy.

Studies conducted over the last decade demonstrated variable therapeutic efficacy of angiotensin converting enzyme (ACE) inhibitor on the progression of glomerular diseases, including IgA nephropathy. In this study, among patients with biopsy-proven IgA nephropathy, 53 patients in whom creatinine clearance had been monitored over 5 yr were recruited for study. These patients were classified into two groups according to whether or not renal function had declined as determined by the slope of creatinine clearance against time: group 1 had stable renal function; group 2 had declining renal function (average: -6.7 +/- 1.3 ml/min/yr). 21 of 53 patients were treated with ACE inhibitor and followed for 48 wk. Gene polymorphism consisting of insertion (I) or deletion (D) of a 287-bp DNA fragment (presumed to be a silencer element) of the ACE gene was determined by PCR. 46 age-matched individuals without history of proteinuria were analyzed as controls. The DD genotype was significantly more frequent in group 2 (43%) than in controls (7%) or group 1 patients with stable renal function (16%). 48 wk after ACE inhibitor administration, proteinuria significantly decreased in patients with DD genotype but not in those with ID or II genotypes. The results indicate that deletion polymorphism in the ACE gene, particularly the homozygote DD, is a risk factor for progression to chronic renal failure in IgA nephropathy. Moreover, this deletion polymorphism predicts the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function.

Adult↗
PubMed1994

Angiotensin II type 1 receptor gene abnormality in a patient with Bartter's syndrome.

Administration of a selective angiotensin I type 1 receptor (AT1) antagonist in animals not only nullifies the vasopressor action of angiotensin II, but also induces chloriduria and kaliuria, juxtoglomerular apparatus (JGA) hypertrophy and hyperreninemia, features characteristic of human Bartter's syndrome. We, therefore, explored the possibility that Bartter's syndrome may involve an AT1 abnormality. Using a pair of AT1-specific oligonucleotide primers and two different DNA polymerases (Taq and Pfu), we amplified the approximately 1 kb AT1 coding region of genomic DNA isolated from leukocytes of five patients with Bartter's syndrome by PCR and analyzed the sequence of the product. While the sequence of all clones from four patients were identical to that already reported for the normal human AT1 DNA sequence, 50% of the clones from one patient with Bartter's syndrome were found to have A-->G transition at nucleotide 931 which causes an amino acid substitution (arg-->gly) on the carboxy-terminal cytosolic tail of AT1. This mutation was not found in DNA from 50 normal controls which were screened by restriction enzyme digestion pattern of the PCR products of this region. As PCR-amplified AT1 DNA clones from four other individuals with Bartter's syndrome did not display any abnormality in the coding region, the possibility exists that Bartter's syndrome consists of multiple disease entities, where an AT1 gene abnormality represents a specific subgroup of the syndrome and/or some abnormality includes mutations outside of the coding region.

Animals↗
PubMed1992

Analysis of the evolution of angiotensin II type 1 receptor gene in mammals (mouse, rat, bovine and human).

The nucleotide and amino acid sequences for mouse angiotensin II (AII) type 1A and 1B receptors were deduced from their complementary and genomic DNAs. Evolutionary analyses based on the nucleotide sequences of the coding region of AII type 1 receptor genes indicated that the duplication event of the type 1 gene occurred 24 +/- 2 million years ago before the divergence between the rat and mouse but after the divergence between rodents and the human/artiodactyls couple. This conclusion was consistent with the results of genomic Southern blot analyses, which revealed that the mouse and rat possess 2 similar but separate genes, whereas the bovine and human have only a single class gene.

Amino Acid Sequence↗
PubMed1992

Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure.

Previous studies in experimental models of progressive renal failure have shown that the capacity of antihypertensive drugs to protect glomeruli from sclerosis is often unpredictable from their effect on systemic blood pressure. The present study was undertaken to ascertain whether this systemic blood pressure-independent structure-preserving effect of antihypertensives, particularly angiotensin II converting enzyme inhibitors (ACEI), is confined to the glomerulus or not, as well as whether this effect is mediated via angiotensin II (Ang II). The following experimental drug regimens were used in the rat model of subtotal nephrectomy (sNPX): so-called triple therapy [TRX; a combination of reserpine 5 mg/liter drinking water (DW), hydralazine 80 mg/liter DW and hydrochlorothiazide 25 mg/liter DW], or ACEI (either captopril, CPL, 600 mg/liter DW, enalapril, ENL, 400 mg/liter DW or lisinopril, LSL, 200 mg/liter DW), or a novel Ang II receptor antagonist (Ang IIR, L-158,809, 20 mg/liter DW). These dosages were identified in pilot studies to be the minimum required to control systemic blood pressure in the early phase up to 12 weeks. In addition, a separate group was treated with a higher dose of L-158,809 (80 mg/liter DW) with equipotent systemic pressor effect. Treatment was initiated eight weeks after subtotal nephrectomy following renal biopsy, and animals were sacrificed at 16 weeks. In ACEI treated rats, carotid arterial wall thickening (WT), defined as ratio of media thickening to radius of outer vessel wall, was similar to normal age-matched control (0.073 in all ACEI treated rats, vs. 0.074 in normal control) and significantly less than with TRX (ratio 0.118) or untreated sNPX (0.130). Even more remarkably, coronary arteriole WT in ACEI-treated rats averaged 0.139, a value less than one half and one third of TRX (0.298) and untreated sNPX control (0.388), respectively. Similar results were obtained for mesenteric artery WT. These findings were closely paralleled by changes of glomerular sclerosis. In untreated sNPX control rats, glomerular sclerosis increased from biopsy to autopsy specimens by an average of 458%. Although TRX dampened the degree of increase in sclerosis to on average 212%, this protective effect was far less than that achieved by ACEI. In the latter, sclerosis increased on average only 65% from biopsy to autopsy. Although all ACEIs were more effective than TRX, captopril and lisinopril groups showed greatest benefit at these doses. Ang IIR also protected renal and extrarenal structures with 34% increase of sclerosis index in low dose and WT 0.088, 0.117 and 0.112, respectively in carotid, mesenteric and coronary arteries.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1992

Dietary fatty acid modulates glomerular atrial natriuretic peptide receptor.

Modification of dietary fatty acid (FA) has been shown to affect the incidence of hypertension and coronary artery disease. We studied whether these effects involve changes in the receptor characteristics of vasoactive substance. Characteristics of atrial natriuretic peptide (ANP) receptors were examined in glomeruli isolated from rats fed a diet containing 5% in weight omega 6, 5% omega 3, 20% omega 6, 20% omega 3 polyunsaturated FA or 20% saturated FA (SFA) for greater than 4 weeks. The FA composition of phospholipids in isolated glomeruli showed an elevation in 20:4 omega 6 (arachidonic acid, AA) in 5% omega 6, 20% omega 6 and 20% SFA, and elevations in 20:5 omega 3 (eicosapentaenoic acid, EPA) in 5% omega 3 and 20% omega 3 groups. The radioligand binding study revealed: (1) in 20% FA group, receptor density (Ro, fmol/mg prot) of ANP was significantly decreased compared to 5% group (262 +/- 13, n = 8 to 120 +/- 13, n = 12) without changes in equilibrium dissociation constant (KD), (2) among high FA (20%) groups, type of FA was essential for determining Ro; higher omega 6 was associated with a lower ANP Ro (177 +/- 11 vs. 103 +/- 3 fmol/mg prot, P less than 0.05) and KD (0.43 +/- .04 vs. 0.27 +/- .02 nM, P less than 0.05). To examine whether the alteration in receptor characteristics is mediated by FA, effects of FA were examined in vitro. In cultured mesangial cells, AA, but not EPA, decreased Ro of ANP receptors (48.7 +/- 4.8% of control, P less than 0.05) without affecting KD.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Evidence for a pathogenic linkage between glomerular hypertrophy and sclerosis.

Primary renal disease of immunologic or nonimmunologic mechanisms induces loss of substantial nephron population. It is presumed that the initial loss of functioning nephrons causes alterations of function and metabolism in remnant nephrons, which per se are self-inflictive, leading to further loss of nephrons. The ultimate outcome of this vicious cycle is the end-stage kidney. The potential role of various pathophysiologic mechanisms has been explored. These studies have shown a tight link between glomerular hypertrophy and sclerosis. Analysis of individual glomeruli show a biphasic pattern of these two parameters. Early development of glomerular sclerosis takes place along with the hypertrophy of the glomerulus, and further advancement of sclerosis occurs with shrinkage in glomerular size. Thus, we propose that, after initial nephron loss, the remnant glomeruli are exposed to increased growth-promoting factors, which are self-inflictive in nature due to their capacity to produce excessive amounts of extracellular matrix in the mesangial area. When the excessive matrix obliterates the glomerular capillary lumen, a typical sclerotic lesion appears. This is a vicious and accelerating process, since sclerosis induces further reduction in the nephron population, thereby imposing greater influence of growth-promoting factors even on glomeruli that are initially resistant.

Aging↗
PubMed1991

Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on glomerular lesions.

We tested the effect of angiotensin I converting enzyme inhibitor (ACEI) on established glomerular sclerosis. Starting eight weeks after subtotal nephrectomy (sNPX), rats were given enalapril for four weeks in a dose of 50 (Group II, N = 5) or 200 mg/liter drinking water (Group III, N = 5). A third group of sNPX rats not given ACEI served as control (Group I, N = 10). Glomerular sclerosis index (S1, 0 to 4 scale) was assessed three-dimensionally on serial thin sections for individual glomeruli at biopsy (Bx, 8 weeks), and divided into four different ranks of severity and compared to autopsy (Ax, 12 weeks). In Group I control rats, 48% of the glomeruli at Bx had SI between 0 and 1 (rank 1, average: 0.49 +/- 0.06), 36% between 1 and 2 (rank 2, average: 1.53 +/- 0.06), 9% between 2 and 3 (rank 3, average: 2.45 +/- 0.12) and 7% between 3 and 4 (rank 4, average: 3.54 +/- 0.10). Glomeruli of the same rats at Ax were ranked according to severity of sclerosis, and then divided into percentile groups, corresponding to the percent of distribution at Bx. The 48% least sclerotic glomeruli at Ax had average SI of 0.69 +/- 0.08, the next 36% 2.58 +/- 0.11, and next 9% 3.97 +/- 0.02 and the most sclerotic 7% 4.00 +/- 0.00. Thus, sclerosis advanced during the last four weeks after biopsy in all glomeruli, with more accelerated progression occurring toward later stages of sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Glucocorticoid activates glomerular antioxidant enzymes and protects glomeruli from oxidant injuries.

We examined the effect of glucocorticoid on intrinsic glomerular antioxidant enzyme (AOE) activities. Munich-Wistar rats were treated with daily i.p. injection of vehicle or methylprednisolone [MP, 15 mg/kg body wt, (MP15)] either for three days or nine days. Glomeruli isolated from rats given MP15 had significantly higher activities of total (T-) and manganese (Mn-) superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase than vehicle-treated rats (P less than 0.05). MP15-treated rats were subjected to intrarenal arterial infusion of hydrogen peroxide (35 mumol over 1 hr). Values for urinary protein excretion rate (UprV) after hydrogen peroxide infusion were markedly lower in rats pretreated with MP15 for both three days and nine days than in untreated rats (109 +/- 18 and 55 +/- 24 vs. 416 +/- 73 micrograms/min, respectively, both P less than 0.005). To test whether the same therapeutic intervention attenuates reactive oxygen species (ROS)-mediated glomerular injury in another model, rats given a single i.v. dose of puromycin aminonucleoside (PAN) (50 mg/kg body wt) were treated with daily i.p. injection of vehicle or MP15. Two days after PAN administration, when compared to vehicle-treated controls, PAN rats given MP15 had significantly higher activities of Mn-SOD, GSH-Px and catalase. After eight days of PAN injection, T- and Mn-SOD activities were, likewise, significantly higher in MP15- than vehicle-treated PAN rats. PAN rats given MP15 also had substantially less proteinuria, compared to PAN rats given vehicle alone, UprV averaging 32.3 +/- 9.4 versus 159.0 +/- 13.8 mg/24 hr (P less than 0.05). Elevated glomerular malondialdehyde (MDA) level characteristic of PAN rats was absent in rats treated with MP15. Moreover, epithelial foot process fusion and cell vacuolization seen in vehicle-treated PAN rats were markedly attenuated in MP15-treated PAN rats. These data indicate that the mechanism for therapeutic effect of glucocorticoids on ROS-mediated renal injuries includes an enhancement of endogenous glomerular AOE activities, which attenuates lipid peroxidation of glomerular tissue.

Animals↗
PubMed1991

Role for "uremic toxin" in the progressive loss of intact nephrons in chronic renal failure.

We studied the effect on the progression of glomerular sclerosis of two different experimental maneuvers, peritoneal dialysis and oral adsorbent, which remove circulating substances in different fashions. Munich-Wistar rats with established glomerular sclerosis, verified by renal biopsy analysis at seven weeks after subtotal nephrectomy, were treated for four weeks with either peritoneal dialysis (PD) or oral charcoal adsorbent (AST-120). Treatment was initiated at eight weeks. Rats were paired in treatment and control groups according to the similarity in the degree of sclerosis determined at biopsy with a minimum of 50 glomeruli analyzed. Systolic blood pressure and BUN and creatinine clearance, measured at seven to eight weeks, were not different among groups. In Group 2 rats, PD was performed with 1.5% dextrose for eight one-hour cycles, six days per week, while Group 1 control rats had zero indwelling time of the dialysate. Group 4 rats received AST-120, an oral adsorbent charcoal, mixed 5% by weight with standard rat chow and given ad libitum from 8 to 12 weeks after subtotal nephrectomy, while control Group 3 rats received only rat chow. Whole kidney GFR at 12 weeks was significantly higher in Group 2 PD versus Group 1 control (0.50 +/- 0.08 vs. 0.30 +/- 0.05 ml/min, P less than 0.05). There was no statistical difference for BUN and whole kidney creatinine or inulin clearance in Group 4 AST-120 treated versus Group 3 control rats. Light microscopic studies in autopsy specimens revealed that both PD and AST-120 attenuated progression of glomerular sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Characterization of myosin heavy and light chains in cultured mesangial cells.

Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that postconfluent mesangial cells in primary culture expressed three myosin heavy chains (MHCs), 204 kD, 200 kD and 196 kD, in a manner similar to that of smooth muscle cells. The MHCs of 204 kD and 200 kD in mesangial cells reacted positively with antibodies raised against bovine aorta smooth muscle myosin while the 196 kD MHC reacted positively with antibodies against platelet myosin. Moreover, the combined content of the MHCs in cultured mesangial cells was remarkably similar in amount to that in cultured aortic smooth muscle cells. After three passages, cultured mesangial cells expressed only the 196 kD MHC as has been reported for cultured smooth muscle cells. Two phosphorylated proteins were found in the immunoprecipitate after incubation of the cell extract with antibodies against platelet myosin: a MHC of approximately 200 kD and myosin light chain (MLC) of 20 kD. The level of MLC phosphorylation was quantitated by scanning densitometry of autoradiograms. Arginine vasopressin (AVP) at 100 nM induced MLC phosphorylation with a maximum effect at 10 minutes. AVP enhanced MLC phosphorylation in a dose dependent manner: maximum response was observed with 100 nM and half maximum, at 3.5 nM. Similarly, angiotensin II (100 nM), endothelin-1 (10 nM) and the calcium ionophore, A23187 (1 microM), significantly enhanced MLC phosphorylation. Thus, although the expression of MHC was altered in quality after mesangial cells were placed in culture, the cells remained rich in myosin content and had an intact regulatory system for contraction which responded to a variety of vasoconstrictive agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Down-regulation of endothelin-1 receptors by protein kinase C in streptozotocin diabetic rats.

The vasoconstrictor response is defective in diabetes mellitus (DM). Activation of protein kinase C (PKC) is also known to prevail in diabetes mellitus, and it is thought to be secondary to abnormal diacylglycerol metabolism. To ascertain whether this PKC activation in diabetes underlies the vasomotor defect by regulating biological receptors, we studied the characteristics of the receptor for endothelin (ET), "the vasoconstrictor of injury." For this purpose, diabetes was induced in rats by intravenous streptozotocin. One to 2 weeks after streptozotocin treatment (average glucose at time of experiments: 518 mg/dl), glomeruli were isolated and assessed for ET receptor and PKC activity. ET receptor characteristics were also assessed following infusion of a specific PKC inhibitor, 1-(5-isoquinolinesulfonyl)piperazine (CI). For comparison, nondiabetic controls with and without PKC inhibitor were studied. No differences in high-affinity ET-1 receptor (ER-1) characteristics were found among the diabetic and normal rats. In contrast, receptor density for the lower-affinity receptor (ER-2) was significantly depressed in DM without changes in the equilibrium dissociation constant. Infusion of CI 20 min before glomerular harvesting did not affect the glomerular PKC activity in controls (particulate: 28.0 +/- 4.0% of total activity to 22.0 +/- 3.9%, n = 3). In contrast, in diabetes mellitus rats infused with CI, PKC activity decreased (particulate: from 44.7 +/- 2.9% of total activity to 18.5 +/- 3.2%, n = 3, p less than 0.05). This CI-induced suppression of PKC in DM was accompanied by complete reversal in down-regulation of ER-2 receptors. Thus, DM is characterized by down-regulation in low-affinity ET-1 receptors. Furthermore, this receptor down-regulation can be reversed by abolishing abnormally enhanced PKC activity. These results indicate that abnormal activation of PKC may underlie the profoundly vasodilative status and defective vasoconstrictor response characterizing DM.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Renal sympathetic nerves modulate glomerular ANP receptors and filtration.

We examined characteristics of atrial natriuretic peptide (ANP) receptors in glomeruli isolated from subacutely (3-5 days) denervated (DNX) and contralateral nondenervated (non-DNX) kidneys of normal rats (NL) and rats subjected to water deprivation for 48 h (WD). Total ANP receptor density in DNX kidneys of WD rats, measured by competitive inhibition binding between 125I-labeled ANP and ANP, was twofold higher than non-DNX kidneys (726 +/- 96 vs. 384 +/- 32 fmol/mg protein, P less than 0.05). Equilibrium association constant (Ka) was not significantly different (2.33 +/- 0.43 vs. 3.34 +/- 0.78 x 10(9) M-1). In NL rats, there was no difference in ANP receptor density between DNX and non-DNX kidneys (244 +/- 20 and 264 +/- 16 fmol/mg protein). Production of guanosine 3',5'-cyclic monophosphate (cGMP), a putative second messenger of ANP, in response to ANP (10(-7) M) in glomeruli isolated from DNX was significantly larger than non-DNX kidneys of WD rats. To determine whether these changes in ANP receptors have functional consequences in vivo, glomerular capillary ultrafiltration coefficient (Kf) was assessed by micropuncture technique in WD Munich-Wistar rats. In DNX kidneys, ANP infusion (4 micrograms.kg-1.h-1) significantly increased whole kidney glomerular filtration rate (GFR) and single-nephron (SN) GFR (0.64 +/- 0.06 to 0.89 +/- 0.17 ml/min and 25 +/- 2 to 33 +/- 2 nl/min, respectively; n = 7) and Kf (1.26 +/- 0.29 to 2.18 +/- 0.41 nl.min-1.mmHg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cyclosporine promotes glomerular endothelin binding in vivo.

It has previously been shown that administration of cyclosporine causes a prompt (within 15 min after infusion) increase in circulating level of endothelin 1 and a pattern of glomerular hypoperfusion and hypofiltration which can be ameliorated with antiendothelin antibody. We now show that 60 min after cyclosporine, serum endothelin 1 level falls to less than 2.55 +/- 0.31 pg/mL (N = 6), a value comparable to that found in normal animals (less than 2 pg/mL). The study presented here also examines whether sustained cyclosporine-induced glomerular dysfunction is associated with altered endothelin receptor characteristics. Saturation and competitive inhibition binding studies in isolated glomerular membranes showed two binding sites. Of these, the density of the low-affinity site was affected by cyclosporine treatment (851 +/- 117 versus 425 +/- 61 fmol/mg of protein; P less than 0.05; N = 6) without a change in equilibrium dissociation constant, KD. The high-affinity site was not affected. The receptor characteristics of another vasoconstrictor, angiotensin II, were not affected by cyclosporine. In addition, there was no difference in endothelin binding sites in hepatic tissue between cyclosporine and control rats. These results raise the intriguing possibility that cyclosporine-induced glomerular dysfunction involves upregulation of endothelin binding sites and that altered endothelin receptors appear specific to the kidney.

Animals↗
PubMed1991

Reactive oxygen metabolites cause massive, reversible proteinuria and glomerular sieving defect without apparent ultrastructural abnormality.

To identify the specific in vivo renal effect of reactive oxygen species (ROS), hydrogen peroxide (H2O2) was infused directly into the left renal artery in Munich-Wistar rats. H2O2 (5 to 50 mumol over 1 h) induced a dose-dependent increase in urine protein excretion rate in infused kidneys, reaching a maximum at the dose of 35 mumol (on average, a 60-fold increase from baseline). The H2O2 (35 mumol)-induced proteinuria peaked over 1 h and completely normalized by 24 h after the infusion. Electrophoresis revealed that the urine protein is primarily of glomerular origin. Fractional clearances of graded-size neutral dextran of larger molecular radii, an index of glomerular size selectivity, were significantly and substantially elevated immediately but normalized by 24 h after the infusion. GFR and RPF rate remained unchanged throughout the entire time course examined. The H2O2-induced proteinuria was largely prevented by pretreatment with catalase (20 mg, iv) or deferoxamine (30 mg/100 g body wt, iv). Thus, iron-dependent metabolites of hydrogen peroxide appear to be involved in this proteinuria and glomerular size-selective defect. Light and electron microscopy, including determination of anionic site density at lamina rara externa of glomerular capillary wall by polyethyleneimine staining, did not reveal any appreciable abnormality throughout the study period, including at the peak of proteinuria. Thus, ROS can cause massive, reversible proteinuria by inducing a molecular size-selectivity defect of the glomerular capillary wall without apparent ultrastructural abnormalities. The results raise the possibilities: (1) that persistent proteinuria of a variety of renal diseases may reflect persistence of pathogenic ROS acting on glomeruli because the potent proteinuric effect of ROS can be transient (2) that the light and electron microscopy abnormalities in glomeruli of ROS-induced renal injuries reported thus far may have no direct causal linkage to proteinuria; and, finally, (3) ROS-induced reversible proteinuria may relate to the mechanism of clinical functional proteinuria, which involves increased oxygen and ROS metabolism, e.g., exercise-induced proteinuria.

Animals↗