Polymorphism of renin-angiotensin system genes in progressive IgA nephropathy

Summary: Clinical studies revealed that angiotensin converting enzyme (ACE) inhibitor reduces proteinuria and attenuates progressive decline in renal function in IgA nephropathy. Recent studies by us and others have demonstrated that the homozygote of the D allele (DD) of the ACE insertion/deletion (I/D) polymorphism is a potential risk factor for poor prognosis in IgA nephropathy, and that this deletion polymorphism predicts the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function in patients with the nephropathy.     

Comparison of Higher Dose of Losartan Treatment with Losartan Plus Carvedilol and Losartan Plus Ramipril in Patients with Glomerulonephritis and Proteinuria

Background. Proteinuria may cause a worsening of accompanying renal disease or even lead to glomerulosclerosis. There is no data about the effect of carvedilol on patients with proteinuric (>0.5 g/day) glomerulonephritis. This study aimed to compare the effects of carvedilol with ramipril and losartan in patients with proteinuric glomerulonephritis. Methods. Twenty-one glomerulonephritis patients were followed for 12 months. Patients were divided into three groups. All patients were treated with losartan 50 mg once daily for two weeks. After two weeks (baseline), patients were given additional medications: 50 mg losartan, 5 mg ramipril, and 25 mg carvedilol were given additionally to the patients in groups 1, 2, and 3 respectively. Results. Baseline mean proteinuria values of patients in groups 1, 2 and 3 were 1.6 ± 1.1 g/day, 2.1 ± 1.3 g/day, and 1.4 ± 1.2 g/day, respectively. These values decreased to 0.5 ± 0.7 g/day, 0.6 ± 0.7 g/day, and 0.9 ± 0.9 g/day, respectively, at the end of the 12^th month. These results were statistically significant only in group 1 (p = 0.04). The rational variation of proteinuria between the first and 12^th month of losartan, ramipril, and carvedilol were ?61%, ?62%, and ?27%, respectively. The decreases in blood pressures between baseline and the first, sixth, and twelfth-month measurements were significant in all groups. Conclusions. Thee results showed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (AT1ras) provide marked decreases in proteinuria, making their use indisputable in patients with glomerulonephritis. Carvedilol was not found to be as effective as ACEIs and AT1ras in decreasing proteinuria and preserving renal function.     

Genetic polymorphisms of the renin-angiotensin system and complications of insulin-dependent diabetes mellitus.

OBJECTIVE: Patients with insulin-dependent diabetes mellitus (IDDM) have a high risk of developing diabetic nephropathy, retinopathy and cardiovascular diseases. The contribution of gene polymorphisms of the renin angiotensin system to these complications is controversial and may differ among populations. METHODS: In 257 Dutch IDDM patients (188 with urinary albumin excretion (UAE) <30 mg/24 h), logistic regression analysis was used to study the relationships among, on the one hand, the insertion/deletion gene polymorphism of the angiotensin-converting enzyme gene (ACE-ID), the M235T gene polymorphism of the angiotensinogen gene (AGT-M235T), and the A1166C gene polymorphism of the angiotensin type 1 receptor gene (AT1-A1166C), and, on the other hand, UAE, retinopathy, hypertension, and coronary heart disease. RESULTS: The T-allele of the AGT-M235T polymorphism was associated with an increased risk of an elevated UAE (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.06-8.61), but only when interaction with the D-allele of the ACE-ID polymorphism was considered. A previously described positive interaction between the T-allele of the AGT-M235T polymorphism and the D-allele of the ACE-ID polymorphism could not be confirmed. The T-allele was also associated with an increased risk of retinopathy (OR 3.89, 95% CI 1.79-8.47). The CC-genotype of the AT1-A1166C polymorphism was associated with hypertension (OR 3.58; 95% CI 1. 23-10.37). CONCLUSIONS: In a Dutch IDDM population, including 69 patients with (incipient) diabetic nephropathy, the T-allele of the AGT-M235T polymorphism is associated with an elevated UAE and diabetic retinopathy and the CC-genotype of the AT1-A1166C polymorphism is associated with hypertension. A previously described interaction between the AGT-M235T and the ACE-ID polymorphisms could not be confirmed. Since the number of nephropathic patients in this study is small, these conclusions must be interpreted with caution.     

The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. For the Collaborative Study Group.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world. Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial (IDNT), studying the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension. Here we report the study design and baseline patient characteristics. METHODS: To qualify, hypertensive type II patients, age 30-70 years, must have a 24 h urinary protein excretion of >900 mg and a serum creatinine 90-265 micromol/l (1.0-3. 0 mg/dl) in women and 110-265 micromol/l (1.2-3.0 mg/dl) in men. Three treatment arms include irbesartan, placebo and amlodipine, with every attempt made to achieve similar blood pressure levels in all treatment arms. A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide. The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. RESULTS: The baseline characteristics of the study subjects are: age 59+/-8 years, duration of diabetes 15+/-9 years, height 168+/-11 cm (5 ft 6 in), weight 87+/-19 kg (192 lb), body mass index 31+/-7 kg/m(2), blood pressure 156+/-18 mmHg/85+/-11 mmHg, serum creatinine 150+/-53 micromol/l (1.7+/-0.6 mg/dl), creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day.     

Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is a complex phenotype resulting from underlying kidney diseases of different etiologies as well as from environmental and genetic factors. The responsible genes influencing the development and rate of progression to ESRD have yet to be defined. We examined an association of the three renin-angiotensin system (RAS) gene polymorphisms with renal disease and progression to ESRD in dialyzed patients. METHODS: Genotyping was performed in 745 ESRD patients and 520 control subjects for the angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms using polymerase chain reaction and gel analysis. RESULTS: Allele and genotype frequencies of the ACE polymorphism did not differ significantly between ESRD patients and controls. The patient group showed an increased frequency of the T allele of the AGT polymorphism (P = 0.02) and the C allele and CC genotype of the AT1R polymorphism (P<0.01). There was an association of the AT1R gene polymorphism with the progression of renal disease to end-stage failure. The time from diagnosis to the onset of ESRD was significantly shorter in patients carrying the C allele than in subjects with the homozygous AA genotype (4.7 years vs 12.6 years, P<0.001). The observed effect was not associated with hypertension in studied subjects. CONCLUSION: The results of our study demonstrate the association between the AT1R A/C polymorphism and renal disease progression. The CC/AC genotype of this polymorphism might serve as a predictor for early ESRD and might be useful in planning therapeutic strategies for individual patients.     

The benefits of renin-angiotensin blockade in renal transplant recipients with biopsy-proven allograft nephropathy.

BACKGROUND: Allograft nephropathy, regardless of aetiology, leads to progressive renal injury and eventual graft loss. In native kidney disease, treatment of hypertension, in particular with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has proven beneficial in retarding renal function decline. In the present study, we reviewed the clinical course of a renal transplant recipient cohort that was prescribed either an ACEi or ARB for biopsy-proven allograft nephropathy. METHODS: Patients were followed from the time of post-biopsy initiation of ACEi/ARB and were stratified based on biopsy findings. Outcomes of interest included safety, allograft survival, renal function and change in slope of renal function pre- and post-ACEi/ARB. RESULTS: The 5 year allograft survival after biopsy diagnosis of allograft nephropathy was 83%. Serum creatinine was 191+/-97 (86-377) micromol/l at the time of biopsy and 228+/-102 (102-575) micromol/l at last follow-up. The slopes of reciprocal creatinine vs time were used to calculate the decline in renal function and were compared pre- and post-ACEi/ARB. The mean slope+/-SD was -0.06+/-0.21 l/micromol x 10(-3) per month in the 12 months prior to therapy and -0.03+/-0.09 l/micromol x 10(-3) per month following therapy. The absolute difference in slopes was 0.03 (P =<0.0001). CONCLUSIONS: Treatment with ACEi/ARB may be beneficial in the management of allograft nephropathy.     

Treatment options in IgA nephropathy

Summary: IgA nephropathy (Berger's disease), the most common primary glomerulonephritis worldwide, leads to end-stage renal failure in 20–40% of patients after 20 years of clinical disease. No consensus has emerged about treatment to slow or prevent the loss of renal function, and in large part this has been due to a critical lack of understanding of the pathogenetic mechanisms. Several approaches that reduce glomerular scarring and inflammation in other renal diseases, including fish oil supplements, anti-inflammatory agents and angiotensin-converting enzyme inhibitors, have been used, with variable results. For patients reaching end-stage, transplantation has shown excellent long-term outcomes.     

Polymorphisms of the angiotensin converting enzyme and angiotensin II type 1 receptor genes and renal scarring in non-uropathic children with recurrent urinary tract infection

AIM: The aim of this study was to investigate whether the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (A1166C) gene polymorphisms were associated with the renal scar formation secondary to recurrent urinary tract infection in children without uropathy. METHODS: The polymorphisms were investigated by polymerase chain reaction in 97 children (81 females, 16 males; age, 2.5-13 years) with recurrent urinary tract infection and 100 healthy controls as a single centre study. Children with vesicoureteral reflux, bladder dysfunction and other uropathies were excluded. The dimercaptosuccinic acid (DMSA) scan performed at least 3 months after a proven urinary tract infection and the result of the last DMSA was taken into consideration. RESULTS: Renal scarring was found in 30 patients (30.9%) using DMSA scan. The number of urinary tract infection attacks was significantly higher in patients with renal scarring compared with children without scarring (P<0.05). The follow-up period and male/female ratio of patients with or without renal scarring was similar (P>0.05). Age at the first urinary tract infection was lower in the group with scarring. The ACE insertion/deletion genotype distribution and D allele frequency were similar between patients and controls (P>0.05), and in patients with renal scarring and those without renal scarring. Also, the angiotensin II type 1 receptor gene polymorphism was not associated with renal parenchymal damage (P>0.05). CONCLUSION: The results indicated that the ACE insertion/deletion and angiotensin II type 1 receptor gene polymorphisms were not independent risk factors for renal scar formation in recurrent urinary tract infection of paediatric patients without uropathy.     

Haemodynamic modulations in IgA nephropathy

Summary: While a variety of immunologic factors are likely to be involved in the initial acute phlogistic events in IgA nephropathy (IgAN), progression to renal failure occurs through a relatively silent course histologically related to prevalent sclerotic changes. In this phase of IgAN, haemodynamic mechanisms are likely to play the most important role. Among the others, angiotensin II and endothelin 1 are thought to be critical mediators. Angiotensin II promotes mesangial cell contraction, modulates membrane permselectivity and induces glomerular hypertension. Evidence for a local angiotensin II hyperactivity in IgAN (especially in patients at definite risk of progression) has been previously provided by our group. Endothelin 1 is mitogenetic for mesangial cells and increases matrix production. Moreover, it exerts local vasoconstrictor effects and induces mesangial cell contraction, both resulting in glomerular afterload. Again, plasma and urinary endothelin 1 are elevated in IgAN. Moreover, those patients with increased risk of progression show an increased ratio between urinary endothelin 1 and cyclic guanosine 3′,5′ monophosphate (GMP), a local messanger with counterbalancing effects. Several data of clinical benefits of angiotensin-converting enzyme inhibitors in IgAN have been reported. Less is known about the intrinsic mechanism of the antiproteinuric action, either reduction of filtration fraction or changes in glomerular permselectivity. The clinical usefulness of factors counterbalancing endothelin 1 effects, such as nitric oxide donors, remains to be established. A sample of eight IgAN patients with poor prognostic indicators was enrolled to examine the renal haemodynamic effects of angiotensin receptor antagonism, angiotensin-converting enzyme inhibition and administration of an exogenous source of nitric oxide. Study periods (7 days each) were randomized and spaced out by one week wash-out. Data showed that angiotensin receptor antagonism and angiotensin-converting enzyme inhibition were equally effective in modifying renal haemodynamics, but only the latter condition significantly reduced albuminuria, possibly indicating a prevalent action on membrane permselectivity in the short time period of the study. The antiproteinuric effects of nitric oxide donors were strictly confined to patients with increased urinary endothelin 1/cyclic GMP ratio. Finally, each treatment condition was found to be associated with an increased nitric oxide production, which appeared to be an additional factor in modulation of filtration fraction changes.     

No impact of hyperkalaemia with renin-angiotensin system blockades in maintenance haemodialysis patients.

BACKGROUND: Renin-angiotensin system (RAS) blockades, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are well accepted for the cardiorenal-protective benefits added to antihypertensive effects in chronic kidney diseases (CKD), but associated with an increased risk of hyperkalaemia. However, few studies have investigated the effect of RAS blockades on serum potassium in dialysis patients. METHODS: Hyperkalaemia associated with RAS blockades by ACEI and/or ARB was evaluated in 69 patients on maintenance haemodialysis, who underwent a three-period crossover study in four groups (no exposure to RAS blockades, ACEI or ARB alone and ACEI plus ARB treatments), lasting one month in each period. RESULTS: Sixty-two patients completed this prospective 3-month study, and no one stopped the study because of the development of hyperkalaemia and/or complications. Mean serum K was similar among the four periods (no exposure, 5.54+/-0.67 mmol/l; ACEI alone, 5.54+/-0.75 mmol/l; ARB alone, 5.50+/-0.66 mmol/l; ACEI+ARB combination, 5.42+/-0.66 mmol/l) and was also equal when compared between the two groups with and without exposure to RAS blockades (5.48+/-0.68 vs 5.54+/-0.67 mmol/l, P=NS). The incidence of severe hyperkalaemic episodes (>6.0 mmol/l) upon monthly predialysis serum K determination was 25.8% with no exposure to RAS blockades, 29.8% for ACEI alone, 19.6% for ARB alone and 17.7% for ACEI+ARB combination without statistically significant differences among the four periods (P=NS). Among covariables, the degree of Kt/V, intakes of other medications interfering with potassium homeostasis and diabetes mellitus did not result in any significant hyperkalaemic changes during the 3-month study period except anuric patients compared with non-anuric patients (5.58+/-0.69 vs 5.19+/-0.65 mmol/l, P<0.001). CONCLUSION: Neither monotherapy (ACEI or ARB) nor combination therapy (ACEI plus ARB) is associated with the additional risk of hyperkalaemia in patients on maintenance haemodialysis. However, those patients with anuria on RAS blockades warrant the cautious monitoring of serum K to prevent hyperkalaemia.     

Angiotensin II further enhances type IV collagen production stimulated by platelet-derived growth factor and fibroblast growth factor-2 in cultured human mesangial cells

SUMMARY: Angiotensin II (Ang II) is considered to play a role in the development of glomerulosclerosis, which is characterized by excessive accumulation of mesangial matrix after mesangial cell proliferation. We have reported that platelet-derived growth factor (PDGF) and fibroblast growth factor-2 (FGF-2) stimulate type IV collagen production by cultured human mesangial cells (HMC). Although Ang II is well known to have a mitogenic effect in various kinds of cells, its role in the production of extracellular matrix is still undetermined. This study was designed to examine the effect of Ang II and its interaction with PDGF and FGF-2 in type IV collagen production by HMC. Cultured HMC were incubated with Ang II with or without PDGF or FGF-2 for 72 h and type IV collagen, fibronectin and laminin in the cell supernatants were measured. Ang II (10⁻⁶–10⁻⁸) itself did not change the production of type IV collagen, fibronectin, laminin and transforming growth factor-β. PDGF and FGF-2 enhanced type IV production, although they did not stimulate the production of fibronectin and laminin. Ang II further increased the stimulating effect of PDGF and FGF-2 in type IV collagen production in a dose-dependent manner. This effect of Ang II was completely blocked by Ang II type I receptor antagonist (Losartan). These data imply that Ang II is a potent stimulator of type IV collagen production by HMC in the presence of growth factors.     

Lower urinary-interleukin-1 receptor-antagonist excretion in IgA nephropathy than in Henoch-Sch?nlein nephritis.

BACKGROUND: IgA nephropathy (IgAN) and Henoch-Sch?nlein nephritis (HSN) share many clinical, histological and immunological features. It has been postulated that these two conditions have a common pathogenesis and that HSN might be a systemic form of IgAN. Activity of interleukin-1beta (IL-1beta) in urine has been found to be higher in IgAN and HSN patients than in healthy controls. Interaction between IL-1beta and interleukin-1 receptor antagonist (IL-1ra) plays a significant role in the regulation of inflammatory responses. We studied levels of urinary excretion of IL-1beta and IL-1ra in patients with IgAN and HSN. METHODS: Amounts of IL-1beta and IL-1ra excreted in 24-h urine samples collected from 241 IgAN, 26 HSN patients and from 33 healthy controls were determined. Results were expressed as cytokine/creatinine (ng/mmol) ratios. RESULTS: Urinary IL-1beta excretion by the IgAN and HSN patients was no greater than urinary IL-1beta excretion by healthy controls. Urinary IL-1ra excretion by the IgAN patients was lower than urinary IL-1ra excretion by healthy controls (P < 0.05) and by the HSN patients (P < 0.01). In both patients and controls women had significantly higher IL-1ra, IL-1beta excretion levels and IL-1ra/IL-1beta ratios. The differences in urinary excretions of IL-1ra by the healthy controls and by the IgAN and HSN patients were significant in both sexes. Excretion of IL-1beta or IL-1ra did not correlate with excretion of urinary protein, duration of the disease or any histopathological variable. However, histopathological changes in renal biopsy specimens from patients with IL-1ra/IL-1beta ratios above normal were significantly milder than in renal biopsy specimens from patients with low or normal IL-1ra/IL-1beta ratios. CONCLUSION: Urinary IL-1ra levels in IgAN patients were lower than urinary IL-1ra levels in healthy controls or HSN patients, a finding which may indicate that the two diseases have a different pathogenesis. Whether the male predominance in IgAN and HSN and the worse outcomes in males that have been reported previously in IgAN and HSN are connected with the lower excretion of IL-1ra and consequently lower IL-1ra/IL-1beta ratios in male patients than in female patients needs more thorough investigation.     

Effects of anti-hypertensive treatment on graft function and proteinuria in a kidney transplant from an elderly hypertensive donor

Abstract:  Hypertension is a common complication after kidney transplantation and adversely affects graft and patient survival. Strategies for anti-hypertensive therapy in an allograft from a hypertensive donor with arteriolosclerosis and the target blood pressure have not been clearly defined. Here, we report the case of deteriorating transplanted kidney function after anti-hypertensive treatment. A 40-yr-old man had received a kidney transplant from a living relative donor (his 69-yr-old father), who was hypertensive and had severe arteriolosclerosis. The recipient showed good allograft function immediately (s-Cr 1.8 mg/dL); however, blood pressure and proteinuria increased markedly two wk after transplantation (blood pressure 180/90, urinary protein 3.4 g/d). We then started anti-hypertensive agents (a calcium channel blocker and an angiotensin II receptor blocker). Blood pressure and proteinuria were corrected to the normal range within two wk of starting the treatment (blood pressure 130/80, urinary protein 0.3 g/d). However, his kidney function continued to deteriorate (s-Cr 2.7 mg/dL). A biopsy, performed at that time, revealed glomerular collapse, advanced interstitial fibrosis and severe arteriolosclerosis, with no evidence of rejection. These findings could have been the result of renal allograft hypoperfusion. We then reduced the anti-hypertensive agents on day 45 after transplantation and observed improved allograft function within a week (s-Cr 1.6 mg/dL). This case suggests that renal hemodynamic responses may be impaired and renal perfusion may not be appropriately maintained in an allograft with severe arteriolosclerosis at a blood pressure level suitable for the recipient. Anti-hypertensive treatment should be performed carefully when the allograft is from an elderly hypertensive donor.     

Association of angiotensin-converting enzyme insertion/deletion polymorphism with type 1 diabetic nephropathy: a meta-analysis

Objective: This study aimed to systematically evaluate the effect of an angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism on type 1 diabetic nephropathy (DN).

Methods: Cochrane Library, Embase, PubMed, Science Direct, Web of science, Wanfang data, VIP database, China Knowledge Resource Integrated Database, and SinoMed were searched. A total of 17 case–control studies analyzing ACE I/D polymorphism and type 1 DN risk were included in the present meta-analysis.

Results: Overall, a significant increased risk was found in allele comparison (OR?=?1.16, 95% CI?=?1.05–1.28, p?=?0.04), dominant comparison (OR?=?1.56, 95% CI?=?1.14–2.15, p?=?0.006) and homozygote comparison (OR?=?1.52, 95% CI?=?1.06–2.19, p?=?0.02). In subgroup analyses according to ethnicity, the risk of type 1 DN in Asian population was increased in allele comparison (OR?=?1.98, 95% CI?=?1.15–3.42, p?=?0.01), recessive comparison (OR?=?2.48, 95% CI?=?1.51–4.10, p?=?0.0004), dominant comparison (OR?=?3.15, 95% CI?=?1.90–5.23, p?p?=?0.05). However, there was no association between the ACE I/D genetic variants and type 1 DN in Caucasian populations.

Conclusions: Our meta-analysis results indicate that the ACE I/D polymorphism may contribute to type 1 DN development, especially in the Asian groups with type 1 diabetes. The current findings need to be confirmed by future well-designed and larger sample size primary studies in populations with different ethnicities.     

Effects of the angiotensin II type 1 receptor antagonist candesartan,compared with angiotensin-converting enzyme inhibitors,on the urinary excretion of albumin and type IV collagen in patients with diabetic nephropathy

Background. We previously reported that the angiotensin II type 1 receptor antagonist candesartan was effective in reducing blood pressure and microalbuminuria in hypertensive patients with diabetic nephropathy after angiotensin-converting enzyme (ACE) inhibitors were replaced due to side effects. In the present study, the clinical effects of candesartan were investigated and compared with ACE inhibitors in patients with stage 2 or 3A diabetic nephropathy, mainly with respect to the effects on the urinary excretion of albumin and type IV collagen. Methods. Forty-nine patients (26 males/23 females) with diabetic nephropathy (stage 2 or 3A), including normotensive patients, were the study subjects. The patients were treated with either an ACE inhibitor (23 patients) or candesartan (26 patients) for 11 ± 3 months. The urinary excretion of albumin and urinary type IV collagen was measured. Results. Posttreatment blood pressure tended to decrease, but such a decrease did not reach a statistically significant level, nor did it show any intergroup difference. The urinary albumin excretion was positively correlated with pretreatment mean blood pressure and left ventricular mass index, but the urinary type IV collagen excretion did not show such correlations. The urinary albumin excretion decreased significantly after treatment to a similar extent in both groups, whereas the urinary type IV collagen excretion decreased significantly only in the candesartan group. Conclusion. It was revealed that ACE inhibitors and candesartan reduced urinary albumin excretion to a similar extent in patients with diabetic nephropathy. From the results of the present study, it is inferred that the renoprotective effect of candesartan in diabetic nephropathy may partially differ from that of ACE inhibitors.     

Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model

Aim:   Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria.
Methods:   Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4–160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed. In this spontaneously hypertensive rat strain, a genetic mutation in the leptin receptor gene is associated with hyperphagia leading to obesity with metabolic syndrome and eventually to nephropathy.
Results:   No additional blood pressure lowering was observed above 120 mg/kg per day of valsartan, suggesting that a dose of 80–120 mg/kg per day had a maximal effect. Nevertheless, higher doses of valsartan further reduced proteinuria in a dose-dependent fashion suggesting the absence of a maximal dose. Obesity, hyperglycaemia and hypercholesterolaemia were unaffected but hypertriglyceridaemia was partially corrected at various ARB doses.
Conclusion:   ARB improve renoprotection at doses above those required for a maximal effect on blood pressure. The mechanism of the renoprotection obtained at high doses of ARB is yet to be elucidated.     

内皮素受体阻断剂对糖尿病大鼠肾脏血管紧张素Ⅱ1型受体表达的影响

目的：观察糖尿病大鼠肾脏血管紧张素Ⅱ1型（AT1）受体的改变以及内皮素受体阻断剂bosentan对其影响。方法：将SD大鼠建成链脲佐菌素诱导的糖尿病模型,设非治疗组、bosentan治疗组和正常对照组。4周后采用免疫组织化学、Western blot及RT－PCR方法检测肾脏AT1受体基因和蛋白表达。结果：与SD对照组相比,糖尿病大鼠存在明显的蛋白尿和内生肌酐清除率升高,其肾脏AngⅡ水平明显升高,同时伴有AT1受体的mRNA和蛋白表达显著下降。bosentan能显著缓解上述异常。结论：糖尿病大鼠肾脏AngⅡ及AT1受体表达明显异常,bosentan具有治疗作用。