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PubMed1989

A morphological study of experimental proteinuria using a novel form of surface fixation.

Careful ultrastructural studies of the rat model of nephrotic syndrome induced by puromycin aminonucleoside have demonstrated morphological features which are only seen in proteinuric glomeruli fixed without interruption of the blood pressure. These consist of balloon-like swellings bounded by attenuated epithelial cell cytoplasm, with an area of bare basement membrane at the base. A theory of the mechanism of proteinuria was proposed on the basis of these findings. To test the proposed wide validity of that theory, we improved the method of surface fixation and performed similar studies in sequential manner, using chronic serum sickness glomerulonephritis in the rat as a model of proteinuria. Glomeruli were studied by light microscopy, transmission and scanning electron microscopy. The findings were correlated with the level of proteinuria in the 24 h preceding death and with the duration of serum sickness. Epithelial cell 'balloons' are also demonstrated in this model, correlating with the presence of proteinuria, but with slightly different configurations from those seen in puromycin nephrosis. Surface fixation revealed similar balloons in two other models of proteinuria: a graft versus host induced model of systemic lupus erythematosus in the mouse, and chronic streptozotocin-induced diabetes in the rat. A lengthy search failed to find bare basement membranes in any of these models of proteinuria. We conclude, therefore, that the mechanism of proteinuria proposed in puromycin nephrosis does not apply in these models, and we suggest an alternative mechanism by which the 'balloons' may develop, as a further manifestation of the epithelial cell dysfunction which causes foot process effacement.

Animals↗
PubMed1992

Management of proteinuria secondary to penicillamine therapy in rheumatoid arthritis.

To determine if a policy of continuing penicillamine therapy in successfully treated patients with rheumatoid arthritis in the presence of persistent proteinuria, was associated or not with resolution of this adverse effect, a computer record of patients receiving penicillamine for rheumatoid arthritis was searched for patients with persistent proteinuria and the case notes of these patients reviewed. Eleven patients with persistent proteinuria were identified, eight of whom did not have nephrotic syndrome and were continued on penicillamine with close monitoring. In 5 patients proteinuria resolved after 16-21 months; 3 developed peripheral oedema (2) or worsening of pre-existing hypertension and proteinuria (1). In one of these the proteinuria subsequently resolved and one died of unknown cause. Of the 3 initially nephrotic patients, two had resolved at the time of the study. Persistent proteinuria in penicillamine-treated patients with rheumatoid arthritis resolves with continued therapy in the absence of nephrotic syndrome but vigilance is required for the development of any complications.

Arthritis, Rheumatoid↗
PubMed1995

Poststreptococcal glomerulonephritis with the nephrotic range of proteinuria.

In order to characterize the clinical features in poststreptococcal glomerulonephritis (PSGN) in relation to the range of proteinuria, 27 patients with PSGN were divided into 3 groups according to the amount of urinary protein excretion; Group I: with proteinuria over 3.5 g/day (n = 8), Group II: with proteinuria between 1.0 and 3.4 g/day (n = 9) and Group III: with proteinuria less than 1.0 g/day (n = 10). Bed-rest was ordered until proteinuria decreased to less than 1.0 g/day. The serum creatinine levels in Group I were significantly higher than in Group III both on admission and at discharge, although the duration of hospitalization was longer in the former than in the latter group. Furthermore, the durations of proteinuria and hypocomplementaemia were longer in the former than in the latter. In addition, the former showed a higher systolic blood pressure and a greater expanded extracellular fluid volume expressed as body weight change during hospitalization. However, none of the patients in this study demonstrated any persistent proteinuria or renal function impairment. In conclusion, bed-rest in the acute phase of PSGN might improve the short-term prognosis of PSGN.

Adult↗
PubMed2006

Prognostic value of postoperative proteinuria in cardiac surgery: a pilot study.

BACKGROUND: Proteinuria is a non-specific marker of inflammation that may reflect the glomerular component of systemic capillary leak. The objective of this pilot study was to determine if postoperative proteinuria is associated with adverse outcomes following cardiac surgery with cardiopulmonary bypass. METHODS: Eligible patients were individuals undergoing cardiac surgery with cardiopulmonary bypass who did not have severe pre-existing renal dysfunction. Urine was collected after induction of anesthesia (baseline) and two to four hours after arrival to the intensive care unit (ICU). Proteinuria was measured as random protein creatinine ratio in g.mol(-1). Adverse events were defined a priori as prolonged ICU stay (> or = 90th percentile) and organ dysfunction. The relationship between proteinuria and adverse events was assessed by bivariate (Chi-square or Fisher's exact tests) and multivariable (multiple logistic regression) analyses. RESULTS: The study included 197 (of 243 eligible) patients. Postoperative proteinuria (protein creatinine ratio > or = 30 g.mol(-1)) was associated with prolonged (> or = four days) ICU stay [odds ratio (OR) 7.0; 95% confidence interval (CI) 2.8-17.1] and organ dysfunction (OR 3.9; CI 1.9-8.1). After adjustment for confounders, proteinuria was associated with a 3.2-fold increase in the odds of both prolonged ICU stay (CI 1.1-9.7) and organ dysfunction (CI 1.4-7.0). CONCLUSIONS: Proteinuria two to four hours after cardiac surgery with cardiopulmonary bypass may be a useful marker for systemic capillary leak and adverse postoperative events. Large prospective studies are needed to confirm these findings.

Anesthesia, General↗
PubMed1981

Proteinuria in the acutely diabetic rat and its response to insulin treatment.

The development of proteinuria and its response to insulin therapy in acute experimental diabetes was examined in 11 female rats by sequentially measuring 24 h excretion of glucose and total protein before diabetes, during 5-37 days of acute streptozotocin diabetes, during and after 7-14 days of continuous subcutaneous insulin administration. Induction of diabetes promptly resulted in marked polyuria (78 +/- 9 ml/24 h), and glycosuria (6.6 +/- 0.7 g/24 h), while proteinuria quadrupled (from 4.7 +/- 0.7 to 18.8 +/- 1.8 mg/24 h, p less than 0.001). Concurrent with amelioration of polyuria and glycosuria by insulin treatment, proteinuria decreased strikingly (8.5 +/- 1.2 mg/24 h, p less than 0.001) Polyuria and glycosuria resumed after discontinuing continuous subcutaneous insulin, and proteinuria promptly returned to pretreatment levels (19.0 +/- 2.5 mg/24 h). Similarly decreased proteinuria (8.8 +/- 0.9 mg/24 h) recurred in five rats retreated with insulin after 100 days of diabetes. Elevated proteinuria was not associated with lysozymuria or consistent changes in glomerular filtration rate. The rapid fluctuations in proteinuria attending acute diabetes and its effective treatment suggest that metabolic aberrations of diabetes may directly effect renal handling of proteins.

Acute Disease↗
PubMed2002

Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition.

AIMS/HYPOTHESIS: Proteinuria, reflecting increased glomerular permeability to macromolecules is a characteristic feature of diabetic nephropathy. Nephrin, a 1241-residue transmembrane protein is a key component of the podocyte slit pore membrane and a major contributor of the glomerular filtration barrier. We investigated the expression of nephrin in human kidney tissue from patients with diabetic nephropathy to elucidate its relationship with proteinuria and the effects of anti-proteinuric therapy with angiotensin converting enzyme inhibition. METHODS: Renal biopsies were examined from 14 patients with Type II (non-insulin-dependent) diabetes mellitus and proteinuria who had been randomised to receive treatment with the ACE inhibitor, perindopril (4 mg/day) or placebo for the preceding 2 years. These specimens were compared with control human tissue sections, obtained from areas of normal renal cortex following nephrectomy for malignancy. Proteinuria was measured, specimens were examined histologically for injury and the expression of nephrin messenger RNA was assessed by quantitative in situ hybridisation. RESULTS: Glomeruli from placebo-treated patients with diabetic nephropathy, showed a 62% reduction in nephrin expression compared with control subjects (p=0.0003). In contrast, nephrin RNA in glomeruli from perindopril treated patients was similar to that in the non-diabetic control group. In both placebo and perindopril treated patients, a close inverse correlation was noted between the magnitude of nephrin gene expression and the degree of proteinuria (placebo: r=0.86, p=0.013, perindopril: r=0.91, p=0.004). CONCLUSION/INTERPRETATION: Modulation in nephrin expression is related to the extent of proteinuria in diabetic nephropathy. These changes define, at a molecular level alterations in the glomerulus that occur in relation to proteinuria in diabetes and the effects of anti-proteinuric treatment with ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Proteinuria and metabolic syndrome as predictors of cardiovascular death in non-diabetic and type 2 diabetic men and women.

AIMS/HYPOTHESIS: Proteinuria predicts cardiovascular disease (CVD), but it is unclear whether this is explained by the association of the metabolic syndrome with proteinuria. Therefore, we investigated proteinuria and the metabolic syndrome as independent predictors of CVD death in men and women. METHODS: The cohort comprised 574 non-diabetic men, 707 non-diabetic women, 371 diabetic men and 349 diabetic women, all free of CVD at baseline. Modified World Health Organization criteria were used to define the metabolic syndrome, and a urinary protein concentration of >or=0.1 g/l (or >or=0.2 g/l) to define proteinuria. The endpoint was CVD mortality during the 18-year follow-up. RESULTS: Among non-diabetic men, CVD mortality per 1,000 person-years was as follows: no metabolic syndrome, no urinary protein group: 5.3; no metabolic syndrome, positive for urinary protein: 8.9; positive for metabolic syndrome, no urinary protein: 13.3; and positive for metabolic syndrome and urinary protein: 14.9. For non-diabetic women the corresponding values were: 0.9, 2.3, 4.9 and 7.9, respectively. Among diabetic men, CVD mortality per 1,000 person-years was 15.2, 32.5, 23.6 and 42.0 for the respective groups. Among diabetic women it was 25.3, 38.0, 26.3 and 40.3 (urinary protein in all cases defined as >or=0.1 g/l). In multivariate Cox models including both urinary protein and metabolic syndrome, the hazard ratios (HRs, 95% CI) of proteinuria for CVD mortality were 1.5 (0.9-2.4) in non-diabetic men, 1.8 (0.8-4.2) in non-diabetic women, 1.6 (1.0-2.6) in diabetic men and 1.6 (1.1-2.3) in diabetic women. Urinary protein as a continuous variable was associated with CVD mortality in all groups. The corresponding HRs for metabolic syndrome were: 1.6 (0.9-2.7), 4.0 (1.7-9.7), 1.5 (1.1-2.0) and 1.1 (0.8-1.5). CONCLUSIONS/INTERPRETATION: Proteinuria predicted CVD mortality independently of the presence of metabolic syndrome in non-diabetic and diabetic subjects. Metabolic syndrome predicted CVD mortality in non-diabetic women and in diabetic men, independently of the presence of proteinuria.

Cardiovascular Diseases↗
PubMed1998

A genetic locus susceptible to the overt proteinuria in BUF/Mna rat.

The BUF/Mna (BUF) strain is a high-proteinuria line of rats, and virtually all rats develop overt proteinuria by the age of 20 weeks. Genetic analysis revealed that proteinuria susceptibility was determined principally by two autosomal recessive genes. These findings prompted us to perform genetic mapping of the genes. (BUF/Mna x WKY/NCrj) F1 x BUF/Mna backcross rats were raised and maintained for 40-60 weeks to detect proteinuria. DNAs were extracted from ears of these rats and were examined by linkage study with polymerase chain reaction (PCR) with 132 microsatellite markers. Fifty-three out of 167 rats developed proteinuria. DNAs of 51 out of these 53 rats showed homozygous BUF/BUF genotype in the D13Mgh4 and D13N1 markers located on Chromosome (Chr) 13. The D13Rat1, D13Mgh2, D13Rat13, D13Mgh3, Syt2, Ren, D13Rat25, D13Mit2, D13Mgh5, and D13N2 markers located on the chromosome also showed statistically significant linkage to the development of proteinuria, whereas the other 110 markers showed no linkage. Here we report that a proteinuria-susceptible gene, Pur1, resides on a region flanked by the loci D13Mgh3 and D13Mgh4 on Chr 13.

Animals↗
PubMed2003

The effect of reactive oxidant generation in acute exercise-induced proteinuria in trained and untrained rats.

Exercise-induced proteinuria is a common consequence of physical activity, although its mechanism is not clear. We investigated whether free radicals generated during exercise play a role in post-exercise proteinuria in sedentary and treadmill-running trained rats, separately. Sedentary and trained rats were randomly divided into four sub-groups: control, antioxidant treatment, exhaustive exercise and an exhaustive exercise plus antioxidant treatment group. Antioxidant therapy was applied by intragastric catheter for 4 weeks with vitamin C (ascorbic acid, 50 mg x kg(-1) x day(-1)) and vitamin E (alpha-tocopherol, 20 mg x kg(-1).day(-1)). Twenty-four-hour urine samples were used for measuring protein levels and protein electrophoresis. Thiobarbituric acid (TBARS) and glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities were assayed in blood and tissues. Increased urinary protein levels and mixed type proteinuria in electrophoresis were identified after exhaustive exercise in sedentary rats. Erythrocyte, kidney and muscle TBARS levels were significantly elevated in this group. Antioxidant treatment prevented the increase in urinary protein levels, TBARS levels and the occurrence of mixed type proteinuria after exhaustive exercise in sedentary rats. Exhaustive exercise in trained rats resulted in elevation of urine protein levels and mixed type proteinuria although kidney TBARS levels were not changed compared to those of the trained controls. Antioxidant therapy in trained and exhausted-trained animals resulted in decreased TBARS levels in the kidney but it did not affect urinary-increased protein levels or electrophoresis in exhausted animals. This findings suggest that the exercise-induced oxidant stress may contribute to post-exercise proteinuria in sedentary rats. However, this mechanism may not be responsible for proteinuria in trained rats.

Animals↗
PubMed2002

Risk factors of renal involvement and significant proteinuria in Henoch-Schönlein purpura.

UNLABELLED: Risk factors of renal involvement and significant proteinuria in patients with Henoch-Schönlein purpura (HSP) were retrospectively evaluated by univariate and multivariate analyses. The analysis was performed in 134 patients with HSP. Renal involvement was found in 65 patients (49%) and 97% of the renal involvement was found within 3 months of disease onset. Moderate or severe proteinuria was recognised in 25 patients. A univariate analysis revealed that an age of more than 4 years at the onset, severe abdominal pain with gastrointestinal bleeding, persistent purpura over a month, coagulation factor XIII activity < 80%, and treatment with factor XIII concentrate were associated with developing renal involvement. A multivariate analysis showed that severe abdominal symptoms, an age of more than 4 years, and persistent purpura increased the risk of renal involvement. Risk factors of moderate or severe proteinuria were also examined. The risk factors in a univariate analysis were severe abdominal symptoms, persistent purpura, decreased factor XIII activity, treatment with steroids, and treatment with factor XIII concentrate. Of those, persistent purpura, treatment with factor XIII concentrate, and factor XIII activity < 80% were associated with significant proteinuria in a multivariate analysis. Among the patients with severe abdominal symptoms, factor XIII activity was significantly decreased in patients with significant proteinuria compared to other patients without significant proteinuria. CONCLUSION: Long-term prognosis of Henoch-Schönlein purpura is dependent on the severity of renal involvement. In those patients who have the risk factors of renal involvement, especially significant proteinuria, close attention should be paid to a urinalysis for at least 3 months from the onset of the disease.

Child, Preschool↗
PubMed2002

HLA associations with HBV carriage and proteinuria.

Human leucocyte antigen (HLA) associations have been reported in children with hepatitis B virus (HBV) associated membranous nephropathy (MN). In a previous study, we found an association with HLA DQB1*0603 in black children with HBVMN. To determine whether HLA DQB1*0603 predisposes to HBV carriage and development of abnormal proteinuria, we studied 70 family members of 14 children with HBVMN positive for HLA DQB1*0603. HBV was determined using third generation ELISA, slot-blot hybridisation, and nested polymerase chain reaction. HLA class I antigens were determined using a two-staged lymphocytotoxic test whereas class II antigen typing was done using sequence-specific primers. Abnormal proteinuria was defined by a protein/creatinine ratio > or =0.2. Associations of HLA DQB1*0603 with HBV carriage and abnormal proteinuria were determined using the mean probability ratio (LOD scores). Forty-seven (67%) family members were positive for HBV infection. Nineteen (27%) had abnormal range proteinuria. LOD scores in the study subjects with DQB1*0603 who were HBV negative versus those with DQB1*0603 who were HBV positive was not significant (anti-log sum =2.0559 and average 0.23). When a similar calculation was made for abnormal proteinuria, there were no significant findings (anti-log sum =3.8587 and average 0.43). This lack of association of HLA DQB1*0603 with either HBV carriage or abnormal proteinuria in family members suggests that additional factors may play a role in predisposing children to chronic HBV carriage and the development of MN. We therefore conclude that the main effect of HLA DQB1*0603 that distinguishes family members from HBVMN is the degree of proteinuria, which is a reflection of the severity of glomerular basement membrane damage in the latter.

Adolescent↗
PubMed1999

A practical approach to proteinuria.

Proteinuria is defined as urinary protein excretion exceeding 150 mg/day. It may result from nonpathological (posture, fever, exercise) or pathological (glomerular or tubular) processes. Glomerular proteinuria is an early sign of kidney disease and may also play a role in the progression of glomerular damage. Asymptomatic proteinuria is common; it may be transient or persistent. Transient proteinuria is a benign condition and requires no evaluation. Persistent proteinuria can be the first sign of kidney disease. Persistent proteinuria commonly results from disorders associated with increased glomerular permeability such as nephrotic syndrome, glomerulonephritis (e.g., post-infectious, membranous, membranoproliferative, lupus, IgA), and genetic defects (Alport syndrome, mesangial sclerosis). Tubular disorders should also be considered. Evaluation for the underlying cause is traditional. Whether the early detection and evaluation of proteinuria prevents progressive disease is unknown.

Exercise↗
PubMed2005

Proteinuria reduction: mandatory consideration or option when selecting an antihypertensive agent?

Proteinuria is a known risk factor for both cardiovascular disease and progression of established kidney disease. Observational studies and intervention trials have established that even low levels of albuminuria (microalbuminuria) are associated with increased risk for cardiovascular morbidity and mortality in general, and especially in high-risk populations such as those with diabetes mellitus. People with hypertension are at increased risk for proteinuria and arguably should be treated with regimens that not only lower blood pressure but also reduce proteinuria. Clinical trials indicate that lowering proteinuria in those with chronic kidney disease is associated with reduced risk for progression to end-stage kidney disease and cardiovascular outcomes. Many of these trials employ antihypertensive agents that block the renin-angiotensin-aldosterone system (RAAS), and indicate that these drugs are, in general, more effective than other antihypertensive regimens for reducing proteinuria. In addition, several small studies suggest that nondihydropyridine calcium channel blockers are comparable with angiotensin-converting enzyme inhibitors and more effective than dihydropyridine calcium channel blockers for reducing proteinuria in type 2 diabetics with advanced kidney disease. Based on the combined evidence from epidemiologic and intervention studies, it seems prudent to make proteinuria reduction a mandatory consideration in the selection of antihypertensive regimens.

Antihypertensive Agents↗
PubMed1984

The prognostic significance of proteinuria: the Framingham study.

Despite considerable clinical experience with proteinuria, its prognostic meaning in the ambulatory general population is poorly documented. From a 16-year study of 5209 men and women in the Framingham cohort it is evident that proteinuria, even in casual urine specimens, carries substantial risk with the mortality rate increased threefold. Proteinuria was three times as common in hypertensive persons and also occurred to excess in diabetic patients and in persons with cardiac enlargement. In the absence of these factors, proteinuria was so uncommon that its risk could not be accurately assessed. Among persons with these associated risk factors, those with proteinuria have higher death rates than those without proteinuria. In men, overall mortality and cardiovascular mortality rates remained significantly increased even when other contributors to risk were taken into account. Proteinuria in the ambulatory general population is not a benign condition and carries a serious prognosis. It appears to reflect widespread vascular damage.

Adult↗
PubMed1992

Prognosis for pre-eclampsia complicated by 5 g or more of proteinuria in 24 hours.

Forty-two women with pregnancies complicated by pre-eclampsia and heavy proteinuria greater than or equal to 5 g/24 h were referred for conservative management to the high-risk obstetric unit in the John Radcliffe Hospital, Oxford, over a period of 5 years. Hyperuricaemia preceded the onset of heavy proteinuria in all 42 women. Most of the women had severe hypertension, but none developed eclampsia and there were no major maternal complications. Delivery was necessary within 2 weeks of onset of severe proteinuria in 88.1% of cases, although in some very preterm pregnancies delivery could be deferred for 3 or more weeks. Thirty-five women (83%) were delivered by caesarean section, 91% of whom were delivered urgently before the onset of labour. The high rate of urgent preterm operative delivery underlines the uncertainty of advanced pre-eclampsia and the need for close monitoring if delivery is to be deferred. Perinatal mortality was high; all the perinatal deaths occurred in babies of less than 29 weeks gestation. Despite heavy proteinuria, postpartum recovery was good. Three months after delivery, all but one patient had no significant proteinuria. There was no evidence of residual renal dysfunction. Although the outlook for pre-eclampsia with heavy proteinuria is limited, in a few cases pregnancy can be prolonged for significant periods of time without apparently prejudicing maternal safety and permitting enhancement of maturity at birth. The observations justify cautious conservative management even when heavy proteinuria is present.

Antihypertensive Agents↗
PubMed1995

Proteinuria in NIDDM in south India: analysis of predictive factors.

There are few data on the risk factors for diabetic nephropathy in the Asian Indian population, although several studies have shown a high prevalence of the disease in this ethnic group. This study also aimed to assess the role of hyperglycaemia and hypertension in the causation and course of nephropathy in this population, which has low rates of obesity. Retrospective analysis of two groups of non-insulin dependent diabetic (NIDDM) patients, one without proteinuria (< 100 mg/day, n = 25) and the other with proteinuria (> or = 500 mg/day, n = 25), matched for age, sex, duration of diabetes and body mass index (BMI) was done to study the factors predisposing to proteinuria and also its progression during a 2 year follow-up. Logistic regression analysis showed that the factors contributory to proteinuria were initial HbA1 and initial systolic blood pressure. The average proteinuria during the follow-up was dependent on the initial and average systolic and diastolic blood pressure values. No correlation was seen between cholesterol or triglyceride values and the change in proteinuria. Creatinine clearance deteriorated in the proteinuric group and this was related to the presence of proteinuria and initial diastolic blood pressure. This study emphasizes the importance of blood pressure in the progression of diabetic nephropathy, even in people who have low BMI. Therefore, good control of blood pressure has an important role to play in the management of this condition.

Blood Glucose↗
PubMed2004

Is early-pregnancy proteinuria associated with an increased rate of preeclampsia in women with pregestational diabetes mellitus?

OBJECTIVE: The purpose of this study was to determine whether the rate of preeclampsia in pregnant diabetic women is increased in those women with early-pregnancy proteinuria of 190 to 499 mg/24 hours compared with women with proteinuria of <190 mg/24 hours. STUDY DESIGN: Secondary analysis was performed with relevant data from 194 pregnant women with type 1 and type 2 diabetes mellitus whose condition required insulin and who were enrolled previously in a multicenter trial of low-dose aspirin for the prevention of preeclampsia. The women were assigned to 1 of 3 groups, based on the level of proteinuria at enrollment (13-26 weeks of gestation). Group 1 comprised women with <190 mg protein/24 hours (n=94); group 2 comprised women with 190 to 499 mg protein/24 hours (n=35); and group 3 comprised women with >/=500 mg protein/24 hours (n=65). The rate of preeclampsia, according to strict predefined criteria, was then determined. RESULTS: The rate of preeclampsia was not increased statistically significantly in patients with early-pregnancy proteinuria of 190 to 499 mg/24 hours (7/35 women; 20%) when compared with women with proteinuria of <190 mg/24 hours (16/94 women; 17%). CONCLUSION: We did not find an increased rate of preeclampsia in women with pregestational diabetes mellitus with early-pregnancy proteinuria of 190 to 499 mg/24 hours when compared with women with pregestational diabetes mellitus with proteinuria of <190 mg/24 hours.

Adult↗
PubMed2001

Renal tubulointerstitial damage caused by persistent proteinuria is attenuated in AT1-deficient mice: role of endothelin-1.

Using angiotensin II (AngII) type 1A receptor-deficient mice [AT1(-/-)], in which we induced protein overload nephropathy, we explored the potential implication of AngII and endothelin-1 (ET-1) in the tubulointerstitial damage because of persistent proteinuria. At day 7, AT1(-/-) showed marked proteinuria to a similar extent to that of wild-type mice (WT). However, at day14, AT1(-/-) had significantly less proteinuria, renal damage, transforming growth factor-beta, and matrix mRNA expression and mortality. AT1(-/-) also showed a significant diminution in the activation of the transcriptional factors nuclear factor-kappaB and AP-1. Unexpectedly, AT1(-/-) had a higher interstitial infiltration than WT. The administration of the angiotensin-converting enzyme inhibitor quinapril to WT caused a marked improvement in proteinuria and renal lesions, resembling that seen in untreated AT1(-/-). However, the interstitial infiltration persisted in AT1(-/-) when treated with quinapril. Because ET-1 may participate in the recruitment of mononuclear cells, we also studied the implication of this peptide. AT1(-/-) had a significantly higher ET-1 expression in tubular epithelial cells than WT. The administration of the dual ETA/ETB antagonist bosentan to AT1(-/-) considerably reduced the interstitial infiltrates. Bosentan also exerted a beneficial effect on proteinuria, renal lesions, and mortality in WT. These data show that in overload nephropathy, proteinuria and renal lesions are, to a large extent, AngII-dependent. The up-regulation of ET-1 in tubular epithelial cells in AT1(-/-), associated with interstitial infiltrates, suggests that the combination of drugs interfering with both vasopeptides may be of therapeutic interest in renal diseases with severe proteinuria and tubulointerstitial damage.

Angiotensin-Converting Enzyme Inhibitors↗