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PubMed2002

Prepubertal treatment with angiotensin receptor blocker causes partial attenuation of hypertension and renal damage in adult Dahl salt-sensitive rats.

Recently, we have shown that treatment of stroke-prone spontaneously hypertensive rats with angiotensin inhibitors for a limited time-window before puberty results in an attenuation of hypertensive nephrosclerosis in later life. The aim of this study was to examine the applicability of this therapeutic paradigm to a low-renin model. Dahl salt-sensitive (Dahl-S) rats were fed a high-salt diet from age 6 weeks. Some rats were treated with the angiotensin receptor blocker (ARB) candesartan cilexetil (2 mg/kg/d) from weaning to puberty (age 3-10 weeks), whereas other rats were treated continuously until overt renal damage was seen (age 3-16 weeks). Dahl-S rats on a high salt diet had increased blood pressure (207 +/- 3 vs. 125 +/- 2 mm Hg), proteinuria, and glomerular/vascular histological changes. The prepubertal treatment with ARB resulted in a continued suppression of blood pressure (153 +/- 2 mm Hg) at 16 weeks. Both proteinuria and renal histological changes were significantly (p < 0.05) attenuated, but not completely prevented by the treatment. No significant differences in plasma renin activity, renin mRNA, or AT1/AT2 mRNA were seen between groups. These results suggest that prepubertal treatment affords sustained renoprotection, even in an animal model with a suppressed renin-angiotensin system, and support the notion that appropriate prepubertal intervention may lead to a partial attenuation in the susceptibility to inherited renal diseases.

Angiotensin Receptor Antagonists↗

PubMedDate not supplied

Clinical characteristics and survival in end-stage renal disease patients with arteriosclerosis obliterans.

BACKGROUND: Atherosclerotic disease (ASO) is considered a serious problem in dialysis patients. We tried to clarify the characteristics of ASO and to evaluate its impact on survival. METHODS: Between January 1990 and December 1999, 525 patients with end-stage renal disease were admitted to our hospital. Among these patients, 71 (59 male and 12 female) had ASO. Blood pressure and blood samples were measured before and after hemodialysis, and were compared with the hemodialysis patients without any cardiovascular diseases. Mortality findings were collected until April 30, 2000. RESULTS: Patients with ASO contained a larger percentage of males, hypertension, hyperlipidemia, diabetes mellitus, nephrosclerosis and smoking status. Their serum calcium, serum phosphate, triglyceride and C-reactive protein levels were also higher. During the follow-up period (2.8 +/- 0.2 years), the mortality rate of the patients with ASO was higher than the hemodialysis patients without any cardiovascular diseases. Among the patients with ASO, the significant covariates concerning the cardiovascular mortality rate were age, hyperlipidemia and smoking status according to the Cox Proportional Hazards regression analysis. CONCLUSIONS: Hemodialysis patients with ASO had many traditional risk factors and uremic risk factors. Their survival rate was poorer and dependent on these risk factors.

Adult↗

PubMed2003

Death with functioning graft in living donor kidney transplantation: analysis of risk factors.

BACKGROUND: Death with a functioning graft (DWF) has been reported as a major cause of graft loss after renal transplantation. It has been reported to occur in 9-30%. METHODS: From March 1976 to January 2002, a total of 1400 living donor renal transplants were performed in our center. Out of 257 reported deaths among our patients, 131 recipients died with functioning grafts after a mean period of 53.4 +/- 53.2 months. RESULTS: DWF patients account for 27% of all graft losses in our series. The mean age was 34.9 + 10.6 (range 8-62 years), 98 of them were male and 33 were female. The original kidney disease was GN in 9, PN in 24, PCK in 5 and nephrosclerosis in 8 patients. Acute rejection episodes were diagnosed in 84 patients (63.1). The post-transplant complications encountered were hypertension in 78 patients (59.5%), diabetes mellitus in 30 patients (22.9%), medical infections in 68 (51.5%), hepatic complications in 30 (22.9%) and malignancy in 17 patients (13%). The main causes of death in these patients were infections in 46 (35.6%), cardiovascular in 23 (17.6%), liver cell failure in 15 patients (11.4%) and malignancy in 8 (6.1%). The mean serum creatinine was 2 +/- 0.6 mg/dl at last follow-up before death. CONCLUSION: We conclude that the relatively higher mortality in renal transplantation is, in part, due to co-morbid medical illness, pre-transplant dialysis treatment, and factors uniquely related to transplantation, including immunosuppression and other drug effects. DWF must be in consideration when calculating graft survival.

Adolescent↗

PubMed2006

Seroprevalence of hepatitis B and C viruses in patients with chronic kidney disease in the predialysis stage at a university hospital in Turkey.

BACKGROUND: Hepatitis B (HBV) and C (HCV) viruses are the most common viruses that cause viral infections among the hemodialysis patients. OBJECTIVES: To assess the prevalence of HBV and HCV in predialytic chronic kidney disease (CKD) patients. DESIGN: A cross-sectional study. SUBJECTS: 171 consecutive predialytic CKD patients. MEASUREMENTS: Third-generation micro-ELISA assay was used for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core (anti-HBc) and surface antibody (anti-HBs), secretory form of hepatitis B envelop antigen (HBeAg), antibody to secretory form of hepatitis B envelop antigen (anti-HBe), and ELISA for antibody to hepatitis C virus (anti-HCV). RESULTS: The main causes of CKD were 29.8% diabetic nephropathy, 19.9% chronic glomerulonephritis, 16.3% hypertensive nephrosclerosis, 14.0% unknown, 5.3% amyloidosis, 4.7% autosomal-dominant polycystic kidney disease, 4.1% chronic tubuluointerstitial nephritis, 3.5% malignancies, 1.7% benign prostatic hypertrophy, 0.6% Alport syndrome. The seroprevalence of hepatitis was: HBsAg 10.5%, anti-HBc 36.8%, anti-HBs 28.7%, HBeAg 5.3%, anti-HBe 32.7%, anti-HCV 7% and HBsAg+anti-HCV 0.6%. CONCLUSIONS: The seroprevalence of HBsAg and anti-HCV among predialytic CKD patients was similar to our patients in hemodialysis program.

Adolescent↗

PubMed1995

L-arginine and arginine analogs in progressive renal failure.

This review summarizes the envolving role of L-arginine, the metabolic precursor of nitric oxide (NO), in disease states that produce progressive loss of kidney function. Hypertension and hypertensive nephrosclerosis manifested in the Dahl/Rapp salt-sensitive rat are exquisitely sensitive to oral L-arginine, which can completely prevent hypertension and subsequent renal damage in these rats. L-Arginine also has been shown to decrease glomerular sclerosis in the remnant kidney model and improve renal hemodynamics and function in animal models of diabetes mellitus. Finally, accumulation of inhibitors of NO production occurs in renal failure and may contribute to hypertension in these patients. Understanding the role of L-arginine and the L-arginine:NO pathway in diseases that produce progressive renal failure may provide new approaches to management.

Animals↗

PubMed1986

Gouty kidney associated with membranous nephropathy: participation of renal tubular epithelial antigen.

Histological studies were performed on 3 patients with gout and proteinuria measured at 1.0 g a day or more. Light microscopy revealed diffuse thickening of the glomerular capillary walls accompanied by spike formation and bubble-like appearance as well as tophaceous granuloma in the interstitium, tubular atrophy and benign nephrosclerosis. Immunofluorescence technique showed fine granular deposits of IgG and C3 along the glomerular capillary walls together with the renal tubular epithelial antigen (RTE) in 1 patient. Subepithelial dense deposits were also observed by electron microscopy. These findings suggest that the association of membranous nephropathy should be considered in patients with gout having moderate to severe proteinuria and that RTE may be involved in the pathogenesis of subepithelial deposits in gouty membranous nephropathy.

Adolescent↗

PubMed1989

Captopril, an angiotensin I-converting enzyme inhibitor, decreases proteinuria in hypertensive patients with renal diseases.

A crossover study was planned in order to compare the effects of captopril and slow channel calcium entry blocker (Ca antagonist) on urinary protein excretion in 7 hypertensive patients with renal diseases, including 4 with IgA nephropathy, 2 with lupus nephritis and 1 with benign nephrosclerosis. Captopril decreased urinary protein excretion by 52% without any change in creatinine clearance, while Ca antagonist was having a slight effect on proteinuria even though the drug showed an equivalent antihypertensive effect as captopril. These results suggest that the attenuation of proteinuria induced by captopril may be related to an inhibition of angiotensin II formation and/or a direct action of this drug on protein permeability of glomerular basement membrane.

Adult↗

PubMed1992

Prevalence of microalbuminuria in a large population of patients with mild to moderate essential hypertension.

To determine the prevalence of increased urinary albumin excretion (UAE) in essential hypertension and to establish whether this abnormality is associated with deranged renal function, we have measured UAE in a group of 123 patients with essential hypertension and in 110 normal subjects. Mean arterial pressure (MAP) was 96 +/- 0.6 mm Hg in normal subjects and 121 +/- 0.3 mm Hg in patients with essential hypertension (p less than 0.01). Mean UAE was 8.6 +/- 0.5 in normal subjects and 32.9 +/- 3.3 mg/24 h in patients with essential hypertension (p less than 0.01). Forty percent of patients with essential hypertension manifested a UAE exceeding 30 mg/24 h and had an average UAE of 72.0 +/- 4.7 mg/24 h. MAP in patients with increased UAE was similar to that in subjects with normal UAE (121 +/- 0.5 vs. 121 +/- 0.4 mm Hg). Creatinine clearance was also not different between these two groups (91 +/- 1.8 vs. 94 +/- 1.5 ml/min). No correlation was found between UAE and MAP or creatinine clearance. Long-term prospective studies are needed to extablish whether an increase in UAE may predict future nephrosclerosis in essential hypertension.

Albuminuria↗

PubMed1994

Effect of renal diseases and comorbid conditions on survival in chronic dialysis patients.

International and geographical differences in the survival rates of chronic dialysis patients can be explained by differences in primary renal disease, in the acceptance rate of elderly patients, and in predialysis comorbid conditions. Several studies have shown the effects of these factors on survival. However, in most studies, a large number of patients may leave for renal transplantation or transfer to other centers, so that precise analysis becomes impossible. Although the number of patients in our registry is not so large (n = 1,982), we have few such problems and were able to examine the effects of the above-mentioned factors on patient survival using the Cox proportional hazard model. Hazard ratios (HR) and 95% confidence intervals were 0.739 and 0.366-1.491 in patients with polycystic kidney disease (n = 38), 2.669 and 1.513-4.708 in patients with systemic lupus erythematosus (n = 39), 1.245 and 0.935-1.660 in patients with nephrosclerosis (n = 122), 1.815 and 1.447-2.229 in patients with diabetes mellitus (n = 374), and 1.595 and 1.201-2.117, respectively, in patients with other renal diseases (n = 146) when the HR in patients with chronic glomerulonephritis (n = 1,263) was taken as 1.00. HR and 95% confidence intervals were 1.222 and 1.016-1.470 in patients with one comorbid condition (n = 217) and 1.494 and 1.033-2.160, respectively, in patients with two comorbid conditions (n = 24) when the HR of patients with no predialysis comorbid conditions (n = 1,741) was taken as 1.00. Our data demonstrate the effects of renal diseases and number of predialysis comorbid conditions on the survival in chronic dialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1996

Renal denervation prevents intraglomerular platelet aggregation and glomerular injury induced by chronic inhibition of nitric oxide synthesis.

Nitric oxide (NO) inhibits platelet adhesion and aggregation in vitro. In vivo, chronic inhibition of NO synthesis induces nephrosclerosis and hypertension. Although the pathophysiological mechanism of this glomerular injury has not been clarified, sympathetic nerve activation, a potent procoagulant stimulus elicited by NO inhibition, may play a role. To investigate the role of renal sympathetic nerves in the development of renal injury induced by NG-nitro-L-arginine methyl ester (L-NAME), a specific NO synthesis inhibitor, we examined renal histological changes in four groups of Sprague-Dawley rats: (1) sham operated, vehicle treated; (2) sham operated, L-NAME treated; (3) denervated, vehicle treated, and (4) denervated, L-NAME treated. Following renal denervation or sham operation, L-NAME was administered orally for 4 weeks. Chronic NO inhibition induced platelet aggregation and erythrocyte stasis in the glomerular capillary lumen accompanied by electron-microscopic glomerular injury. Renal denervation abrogated platelet aggregation and glomerular injury in L-NAME-treated animals. Thus, chronic NO synthesis inhibition induced intraglomerular platelet aggregation and glomerular injury, which was attenuated by renal nerve denervation. These results suggest that intrinsic NO may have an antithrombotic effect in the glomeruli and may play a protective role in the progression of glomerular injury possibly mediated by renal sympathetic nerves.

Albuminuria↗

PubMed1996

Increased excretion of tumor necrosis factor alpha and interleukin 1 beta in urine from patients with IgA nephropathy and Schönlein-Henoch purpura.

Urinary proteins (5 mg/ml) collected from a group of 16 patients including 13 with IgA nephropathy and 3 with Schönlein-Henoch purpura (SHP) and from a control group consisting of 6 patients with diabetic nephropathy, 5 patients with hypertensive nephrosclerosis, and 5 healthy hospital staff members were studied for the contents of interleukins (IL) 1 beta, 2, 4, 6, and 12 and tumor necrosis factor alpha (TNF-alpha). Eleven patient with IgA nephropathy or SHP (11/16) but only 1 of the controls (1/16) had TNF-alpha activity in urinary proteins (p < 0.01). The IL-1 beta activity exhibited a similar tendency but to a lesser extent (10 of 16 patients with IgA nephropathy or SHP vs. 2 of 16 with other conditions, p < 0.05). Conversely, the detection rates of IL-2, IL-4, and IL-6 in both groups were not significantly different. IL-12 was not found in any of the samples from both groups. Sera and nonpurified urine samples from the same individuals were also measured for cytokines. IL-1 beta, IL-2, IL-4, and IL-12 were absent in all these samples, but TNF-alpha was found in four of the serum samples from patients with IgA nephropathy. Urinary proteins (2 mg/ml) were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whereby peptides of 52, 49, 45, 34, 30, and 11 kD could be demonstrated in the patients with IgA nephropathy or SHP. Urinary proteins (200 micrograms/ml from patients with IgA nephropathy or SHP exerted a mitogen-like effect on the normal human mononuclear cells, as demonstrated by 3H-thymidine incorporation. In addition, these urinary proteins (400 micrograms/ml) enhanced the proliferative activity of the cultured rat glomerular mesangial cells. The exaggerated proliferation of rat glomerular mesangial cells exerted by urine proteins from 2 patients with active disease was markedly suppressed after treatment with glucocorticoids/cyclophosphamide. These results suggest that patients with IgA nephropathy or SHP can excrete excessive amounts of TNF-alpha and IL-1 beta in the urine. The inconsistent presence of these two cytokines in urine and serum may indicate that they can be produced locally and that they are implicated in the development of mesangial inflammation and glomerular damage.

Adolescent↗

PubMed1986

Experimental basis of angioinfarction for the treatment of renal hypertension.

Collateral circulation and recanalization represent the main problems of organ-ablating renal embolization. Different animal models were used to study the influence of central, peripheral, and capillary occlusion on organ necrosis. The first laboratory experiments were performed to optimize transcatheteral application of the embolization media tested (Gelfoam powder, Histoacryl, Ethibloc). Experiments with the model of a normal rat kidney (n = 400) showed that only capillary embolization homogeneously occluding the entire arterial system resulted in complete organ necrosis, while following central (renal artery ligation) or peripheral (Gelfoam powder) occlusion, areas of intact parenchyma remained. Ethibloc/glucose proved to be the embolization medium best suited for capillary embolization (radiopaque, inert, slow resorption). Studies with the model of unilateral renal hypertension of the rat (n = 146) demonstrated the equivalent therapeutic efficiency on blood pressure of Ethibloc embolization (57% cured, 21% improved) compared to surgical nephrectomy (50% cured, 29% improved), whereas renal artery ligation (85% failed) resulted in minor improvement only. In order to adapt capillary embolization with Ethibloc/glucose to clinical angiographic techniques, we performed angioinfarction of canine kidneys (n = 15): the use of a balloon catheter is mandatory. This guarantees blood stasis during the embolization procedure and avoids embolic reflux. Possible clinical indications of capillary embolization in renal hypertension as a less invasive method are, e.g.: malignant nephrosclerosis; renovascular or glomerulonephritic contracted kidneys, and renal dysplasia. Indications for super-selective vaso-occlusion are renal aneurysms, a-v malformations, and segmental hypoplasia.

Angioplasty, Balloon↗

PubMed1981

Enzymuria (the output of gamma-glutamyl-transpeptidase and of N-acetyl-beta-D-glucosaminidase) in the course of experimental renovascular hypertension.

The urinary output of gamma-glutamyl-transpeptidase (gamma GT) and of N-acetyl-beta-D-glucosaminidase (NAG) was studied with "two-kidney Goldblatt hypertension' 3-6, 16-19 and 30-33 weeks after eliciting high blood pressure. gamma GT excretion rate of normotensive males was higher than that of females, while the activity of the renal tissue was on the same level. gamma GT output of hypertensive males was elevated in the early and in the middle stages of the disease, it was subnormal in the late stage. In females gamma GT output increased in animals with excessively high blood pressure (less than 200 mm Hg) only. gamma GT output correlated with the tissue activity in males only. In all animals there was an inverse, linear correlation between tissue gamma GT activity and the hydroxyproline content. The pattern of the NAG output was similar to that of gamma GT, however, excretion of NAG showed no sex differences and remained high in the late stage of the disease, too. Nephrosclerosis was less pronounced in female Goldblatt rats than in males.

Acetylglucosaminidase↗

PubMed1997

Cardiovascular risk factors and hyalinization of renal arterioles at autopsy. The Honolulu Heart Program.

Nephrosclerosis, commonly found in subjects with hypertension and diabetes, is marked by hyalinization of arterioles and fibroplasia of small arteries in the renal cortex. Cardiovascular risk factors that predicted subsequent hyalinization of renal arterioles at autopsy were identified, using data from the Honolulu Heart Program, a prospective epidemiological study of cardiovascular disease (CVD) in Japanese-American men. Among 8006 participants at baseline, 1381 died between 1965 and 1982; 285 of these had a protocol autopsy, and 150 had assessments of arteriolar hyalinization from renal tissue. Subjects were categorized into four groups on the basis of the number of hyalinized arterioles per square centimeter of renal tissue, and CVD risk factor levels and proportions were compared across these groups with the use of general linear models and logistic regression. Multivariate assessment using logistic regression demonstrated that diastolic blood pressure (DBP) and glucose level were positively associated and alcohol intake was negatively associated with an elevated degree of renal arteriolar hyalinization, independent of other CVD risk factors. The odds ratios for elevated hyalinization associated with a 10-mm Hg increase in DBP, a 20-mg/dL increase in glucose level, and a 30-mL/d increase in alcohol intake were 1.97 (95% confidence interval [CI] = 1.24-3.12), 1.23 (95% CI = 1.07-1.41), and 0.24 (95% CI = 0.11-0.55), respectively. Associations were similar when prevalent cases of CVD were excluded and when autopsy selection bias was taken into account. Renal arteriolar hyalinization was also more strongly associated with atherosclerosis in the larger cerebral vessels (Spearman's r = .59, P < .001) than in the coronary arteries (r = .16, P = .073) and aorta (r = .24, P = .022). Hyalinization was significantly related to cardiovascular-renal mortality, and this association was accounted for by other CVD risk factors. These findings suggest that blood pressure, glucose level, and alcohol intake are independent predictors of hyalinization in renal arterioles and that this type of renal vasculopathy may be a marker for atherosclerosis in other vascular regions, particularly the cerebral vessels. The protective association involving alcohol and the possibility that renal arteriolar hyalinization may be an indicator of cerebral atherosclerosis may warrant investigation in other populations.

Age Factors↗

PubMed2004

Modifier locus on mouse chromosome 3 for renal vascular pathology in AT1A receptor-deficiency.

We previously showed that the phenotype of mice with targeted disruption of the gene encoding the AT1A receptor (Agtr1a), the major murine AT1 receptor isoform, is strongly influenced by recessive genetic modifiers derived from the C57BL/6 or 129 inbred strains. To further evaluate the genetic modifiers on the C57BL/6 background, we performed backcrosses between F1(C57BL/6x129) and C57BL/6 Agtr1a-/- mice and analyzed the progeny, focusing on the development of structural lesions in the renal vasculature. In affected animals, these lesions are characterized by medial thickening of small arteries and arterioles in the kidney that are reminiscent of vascular lesions in patients with nephrosclerosis. Among 180 consecutive progeny, 170 (94%) survived to completion of the study. On masked pathological examination at age 8 months, 86 had intermediate to severe vascular lesions whereas 84 had no detectable lesions. Based on a hypothetical model of a single recessive modifier locus arising from the C57BL/6 background, the observed proportion of affected animals among the backcross progeny was not statistically different from that predicted by chi2 analysis (51% versus 50%; P=0.88). We next performed genomic microsatellite analysis in a subset of 121 backcross progeny using a panel of markers spanning approximately 15 cM intervals across the mouse genome. By 2-point analysis, we found a region spanning 5 cM on chromosome 3, with significant linkage to the development of renal vascular lesions (LOD score: 3.3 to 3.8).

Animals↗

PubMed1990

Differences in blacks and whites with essential hypertension: biochemistry and endocrine. State of the art lecture.

Overall, there is agreement that the origins of hypertension have a genetic basis. The genetic factors interact with environmental factors that influence expression and intensity of the disorder. As summarized in Table 1, there is evidence from the literature to identify pathways for the development of hypertension in blacks. Organ pathology, characteristic of the clinical phenotypic hypertension, consists of increased peripheral vascular resistance and left ventricular hypertrophy, and, particularly in blacks, nephrosclerosis. In this scheme, an intermediate phenotype is a biochemical or endocrine marker of gene expression that participates in the regulation of blood pressure. Intermediate phenotypic characteristics of essential hypertension include sodium sensitivity, adrenergic activity, cation transport, and endocrine function including renin-angiotensin-aldosterone, kallikrein-kinin, and prostaglandin. Another intermediate phenotype to be included in this discussion is insulin resistance. These intermediate phenotypes of cell and subcellular function are regulated by candidate genes. Alternatively, an intermediate phenotype can be expressed in response to another intermediate phenotype. For example, sodium sensitivity could be mediated by the cation transport mechanism of Na,K-ATPase, or insulin resistance could be induced by an elevated level of adrenergic activity. Gene expression of the intermediate phenotype is also modulated by environmental factors such as dietary sodium, potassium, or calcium, and social stresses or patterns of physical activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗

PubMed1992

Frederick Akbar Mahomed.

Frederick Akbar Mahomed was an Englishman of mixed Indian and Irish descent who made substantial contributions to the study of high blood pressure in a short professional life from 1872 to 1884. He was strongly influenced by the previous work of Richard Bright on kidney disease at his own hospital (Guy's Hospital in London) and by the contemporary pathological studies of Gull and Sutton on arteriolar changes in persons with high blood pressure. In detailed clinical studies, he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. He described the constitutional basis and natural history of essential hypertension and pointed out that this disease could terminate with nephrosclerosis and renal failure. His clinical studies were done without the benefit of a sphygmomanometer but with the aid of a quantitative sphygmogram that he had initially developed while a medical student. He described characteristic features of the pressure pulse in patients with high blood pressure and in persons with arteriosclerosis consequent on aging. These pressure wave changes have recently been verified and explained. He contributed to a number of other advances in medical care, including blood transfusion and appendectomy for appendicitis. He initiated the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials. Mahomed died from typhoid fever, almost certainly contracted from one of his patients, at age 35 at the height of his career.

Blood Pressure Determination↗

PubMed1993

Early interstitial changes in hypertension-induced renal injury.

To elucidate the mechanisms of hypertensive renal injury, we investigated the time course and extent of changes in matrix composition, as well as cell proliferation and infiltration in two-kidney, one clip rats. The nonclipped kidneys from hypertensive and sham-operated control rats (n = 5 to 10 in each group) were studied at 7, 14, 21, and 28 days after clipping. Systolic blood pressure was elevated by day 7 (154 +/- 3 versus 111 +/- 4 mm Hg in sham group, P < .001, n = 10 each). Hypertension resulted in an early expansion of the interstitial volume by 37%, whereas hypertensive vascular changes and glomerular injury did not become evident until day 21. Immunofluorescence studies revealed an early interstitial accumulation of collagens I, III, IV, V, VI, and fibronectin by day 7. In contrast, the glomeruli showed a mild to moderate increase in collagens I, III, IV, V, laminin, and fibronectin but not collagen VI later in the established phase of hypertension. Staining for proliferating cell nuclear antigen as a marker of cell replication was increased in tubular epithelial but not interstitial or glomerular cells. A progressive infiltration of macrophages (16 +/- 2 versus 9 +/- 1 ED1+ cells/mm2, P < .05, n = 6) and T lymphocytes (93 +/- 15 versus 74 +/- 7 CD4+ cells/mm2, n = 8) in the cortical interstitium had already occurred by day 7. On the other hand, only macrophages increased in number within the glomeruli. Thus, renovascular hypertension leads to an early tubular cell proliferation, mononuclear cell recruitment, and deposition of matrix proteins primarily within the interstitium. We conclude that the injury producing nephrosclerosis in this model extends far beyond the glomeruli. Both the tubules and the interstitium are actively involved and may be the more important initial sites of injury.

Animals↗