Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition. CONCLUSION: The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.     

Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat

BACKGROUND: Endothelin (ET) and angiotensin II (Ang II) are vasoactive/trophic peptides that may contribute to the progression of diabetic nephropathy. The transgenic (mRen-2)27 rat exhibits overexpression of Ang II at sites of normal physiological expression. Unlike other rat strains, the streptozotocin-induced diabetic Ren-2 rat develops progressive renal pathology associated with a declining glomerular filtration rate (GFR) and provides a convenient model to evaluate the role of these vasoactive peptides in the nephropathic process. METHODS AND RESULTS: Oral administration of either the endothelin A (ETA) and ETB receptor antagonist bosentan or the angiotensin type 1 (AT1) receptor antagonist valsartan for 12 weeks reduced systolic blood pressure (SBP) of nondiabetic and diabetic Ren-2 rats to normotensive levels. Diabetic renal pathology was associated with intense renin mRNA and protein in the proximal tubules and juxtaglomerular cells along with overexpression of transforming growth factor-beta1 (TGF-beta1) and collagen IV mRNA in glomeruli and tubules. With valsartan but not bosentan, renin mRNA and protein in the proximal tubules were not detected. Valsartan but not bosentan reduced TGF-beta1 and collagen IV mRNA and the severity of diabetic renal pathology. A declining GFR with diabetes was attenuated by both treatments. Albuminuria in diabetic rats rose further with bosentan but was reduced with valsartan. CONCLUSIONS: Despite producing normotension, severe diabetic renal pathology was not prevented by bosentan, suggesting dissociation of ET, albuminuria, and hypertension from the structural injury in this diabetic model. The beneficial effects afforded by valsartan therapy strengthen the importance of the local renin-angiotensin system in mediating progressive diabetic renal injury.     

Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial

Despite the beneficial effects of blockade of the renin-angiotensin system in diabetic nephropathy (DN), albuminuria and progression of renal disease are not completely halted by these agents. Therefore, it is necessary to explore potential antiproteinuric and renoprotective effects of innovative therapeutic approaches. This study tested the hypothesis that the combination of pentoxifylline (PTF) with angiotensin II receptor blockers in normotensive patients with type 2 diabetes produces an additive antiproteinuric effect. Sixty-one patients with DN and residual albuminuria despite treatment with the recommended doses of ARB for >1 yr were randomly assigned to receive the addition of 1200 mg of PTF daily (n = 30) or to a control group (n = 31). Baseline characteristics were similar between groups, and correlation analysis showed a significant association between urinary albumin excretion (UAE) and urinary TNF-alpha (R = 0.53, P < 0.001). After 4 mo, albuminuria showed a significant decrease in patients who received PTF, from 900 mg/24 h (466 to 1542 mg/d) to 791 mg/24 h (309 to 1400 mg/d; P < 0.001), whereas no significant changes were observed in the control group: 920 mg/24 h (450 to 1489 mg/d) at baseline, and 900 mg/24 h (428 to 1800 mg/d) at the end of the study. The mean percentage variation of UAE in the treatment and control groups was -16.7 and 5.5%, respectively (between-group comparison, P < 0.001). This additive antiproteinuric effect was not dependent on changes in BP or metabolic control. However, both serum and urinary levels of TNF-alpha also decreased in patients who received PTF, from 6.4 pg/ml (2.1 to 9.7) and 16 pg/mg (8 to 29) at baseline to 4.6 pg/ml (0.4 to 9) and 14.2 pg/mg (3 to 26) at the end of the study, respectively (P < 0.01), without significant variations in control patients. Moreover, regression analysis at the end of the study showed a correlation between the change in UAE and the change in urinary TNF-alpha in patients who were treated with PTF (R = 0.49, P < 0.001). In conclusion, administration of PTF to patients who have type 2 diabetes and are under long-term treatment with an ARB produces a significant additive antiproteinuric effect associated with a reduction of urinary TNF-alpha excretion.     

Expression of renal and vascular angiotensin II receptor subtypes in children

Angiotensin II (Ang II) AT1 receptors modulate most of the known physiological functions of Ang II in the kidney and cardiovascular structures. In contrast, the physiological role of AT2 receptors, which are abundantly expressed in fetal tissues, is not clearly defined. The changes that occur in the expression and distribution of AT2 receptors in the kidney and arteries during the first 2 years of life have not been studied. We have localized and characterized the expression of Ang II receptor subtypes, AT1 and AT2, in the kidney, interlobular arteries, thoracic aorta, and middle cerebral artery, in children during their first 2 years of life, using quantitative autoradiography. Renal glomeruli and middle cerebral arteries expressed exclusively AT1 receptors. In contrast, more than 80% of the Ang II receptors expressed in thoracic aorta and interlobular arteries belonged to the AT2 subtype. These findings demonstrate that the expression of Ang II receptor subtypes in different vascular structures in young children varies according to the tissue.     

Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy

Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. This study tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor (ACE-I) and an Angiotensin-II receptor blocker (ARB) is superior to either drug alone in type I diabetic patients with diabetic nephropathy (DN). A randomized double-blind crossover trial was performed with 8-wk treatment with placebo, 20 mg of benazepril once daily, 80 mg of valsartan once daily, and the combination of 20 mg of benazepril and 80 mg of valsartan. Twenty type I diabetic patients with DN were included. At the end of each treatment period, albuminuria, 24-h BP, and GFR were measured. Eighteen patients completed the study. Placebo values were: albuminuria [mean (95% CI)], 701 (490 to 1002) mg/24 h; BP [mean (SEM)], 144 (4)/79 (2) mmHg, and GFR [mean (SEM)], 82 (7) ml/min per 1.73 m(2). Treatment with benazepril, valsartan, or dual blockade significantly reduced albuminuria and BP compared with placebo. Benazepril and valsartan were equally effective. Dual blockade induced an additional reduction in albuminuria of 43 % (29 to 54 %) compared with any type of monotherapy, and a reduction in systolic BP of 6 (0 to 13) mmHg and 7 (1 to 14) mmHg (versus benazepril and valsartan, respectively) and a reduction of 7 (4 to 10) mmHg diastolic compared with both monotherapies. GFR was reversibly reduced on dual blockade compared with monotherapy and placebo. All treatments were safe and well tolerated. In conclusion, dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN.     

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes: a subanalysis of Japanese patients from the RENAAL study

Background The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study has previously shown losartan to confer significant benefits to patients with type 2 diabetes and nephropathy. The original study of 1513 patients included 96 Japanese patients; the present study is a post-hoc analysis of the effects of losartan in this Japanese subpopulation. Methods This double-blind, randomized study compared losartan (50 to 100 mg once daily) with placebo. The study medication was taken in addition to conventional antihypertensive treatment, and the mean follow-up period for the Japanese patients was 2.8 years. The primary endpoint was the composite of doubling of serum creatinine, endstage renal disease, or death. Secondary endpoints included changes in proteinuria levels. Safety was also evaluated. Results The primary composite endpoint was reached in fewer Japanese patients receiving losartan than placebo (50.0% versus 65.4%, respectively). The treatment effects of losartan were more robust when data were corrected for differences in proteinuria at baseline – a significant relative risk reduction of 45% with losartan (P = 0.0397) was apparent. Treatment benefit exceeded that attributable to blood pressure changes alone. Levels of proteinuria were reduced with losartan compared with placebo, with an overall losartan treatment effect of 37.8% (P < 0.001). Overall, losartan was similarly well tolerated in both the Japanese patients and the total population. Conclusions In Japanese patients with type 2 diabetes and nephropathy, losartan offers renal protection and is generally well tolerated.     

Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II receptor blockers

Aggressive treatment of hypertension is effective in reducing both microvascular and macrovascular complications in type 2 diabetes, and target BP less than 130/85 or 130/80 mmHg are now recommended. Inhibition of renin angiotensin aldosterone system (RAAS) plays an essential role in the treatment of hypertension and diabetes-related complications. Studies focusing on renal end-points suggest that angiotensin-converting enzyme inhibitors (ACE-I) are more effective than other traditional agents in reducing the onset of clinical proteinuria in both type 1 and type 2 diabetic patients with incipient nephropathy, mainly in normotensive ones (secondary prevention). However, several small trials in type 2 diabetic patients with overt nephropathy (tertiary prevention) failed to demonstrate a specific renoprotective role for ACE-I, at variance with type 1 diabetes. Three recent large trials address the question of whether angiotensin II receptor blockers (ARB) prevent the development of clinical proteinuria or delay the progression of nephropathy in type 2 diabetes. The IRMA study showed that irbesartan is more effective than conventional therapy in preventing the development of clinical proteinuria and in favoring the regression to normoalbuminuria for comparable BP control in patients with incipient nephropathy. The IDNT and RENAAL trials showed that ARB are more effective than traditional antihypertensive therapies in reducing progression toward end-stage renal failure (ESRF) in type 2 diabetic patients with overt nephropathy independently of changes in BP. Moreover, a reduction in hospitalizations for heart failure was demonstrated for ARB-treated patients compared with placebo. Furthermore, the LIFE study showed that losartan is more effective than conventional therapy in reducing cardiovascular morbidity and mortality in a cohort of diabetic patients with hypertension and left ventricular hypertrophy. In conclusion, ARB seem to be effective in both preventing renal damage and reducing progression toward ESRF in type 2 diabetic patients. Thus, the guidelines for the prevention and treatment of diabetic nephropathy are now changed. In type 1 diabetes ACE-I are the first-choice drug; in type 2 diabetes, ARB are considered first-choice drugs in secondary prevention as well as ACE-I and have been now elected the unique first-choice drug in tertiary prevention of ESRF. Finally, ARB should be considered as the first-choice drug in cardiovascular prevention too, as well as ACE-I.     

Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients

Introduction Notwithstanding proven renoprotection from RAAS blockade (AB) with ACE inhibitors and ARBs, and despite increasing utilization of AB in the US, we have continued to experience a CKD/ESRD epidemic. Given concerns for iatrogenic CKD/ESRD, we designed a prospective study to analyze the course of eGFR following withdrawal of AB in such patients. Patients Between September 2002 and February 2005, all consecutive CKD patients on AB presenting with >25% increase in baseline serum creatinine were enrolled. eGFR following withdrawal of AB was monitored. The main outcome measures were serum creatinine, MDRD eGFR, and UA/Cr. Results 100 Caucasians, M:F = 52:48, mean age 71.5 years were enrolled. Mean follow up was 26 months. Sixteen patients progressed to ESRD, of whom seven died. In 74, eGFR improved from 23.9 ± 9 (7–47) to 39.2 ± 15.4 (17–89) ml/min/1.73 m² BSA, 26.5 (3–46) months after stopping AB (P = 0.001). The majority of the cohort, 95 patients, had known risk factors: 26 with RAS, 12 hypovolemia, 11 sepsis, 10 NSAIDs/cox II inhibtor use/abuse, 7 CIN, 2 congestive heart failure, 2 obstructive uropathy, and 27 with other medical and surgical causes, including malignancies, postoperative states, and infections. In the 26 with RAS, 5 with higher baseline creatinine −2.1 ± 0.6 versus 1.5 ± 0.4 mg/dL, P = 0.013, progressed to ESRD; 4/5 ESRD patients died after 6.3 months. The remaining five patients (one male and four females), mean age 68 (44–83) years, demonstrated sustained improved eGFR with discontinuation (four) or reduction (one) of RAAS blockade, despite normal renal arteries and the absence of known traditional risk factors. UA/Cr generally increased following withdrawal of AB. Conclusions Worsening azotemia in older susceptible CKD patients on AB, often but not always associated with known precipitating risk factors, remains under-recognized. Sustained improved eGFR often follows the discontinuation of AB. The practising physician should be well aware of these syndromes. Our observations call for further study. No external funding was involved in this study. Institutional review board (IRB) approval was obtained. This work is dedicated to the memory of a pleasant unnamed 74-year-old white woman, with ESRD, who died suddenly at home watching television, probably from a malignant arrhythmia.     

Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance

The renin-angiotensin system with its active metabolite angiotensin (Ang) II has been related not only to hypertension but also to obesity and insulin resistance. Recent evidence obtained in vitro suggests that the type 2 Ang II receptor (AT2R) mediates the trophic action of Ang II on adipocyte differentiation and lipogenesis. We used AT2R(y/-) mice to delineate a potential role of AT2R in adipose tissue development and metabolism. AT2R(y/-) mice had a normal adiposity but displayed a striking adipose tissue phenotype characterized by small adipocytes and an increase in cell number. In muscle, the expression of several genes involved in lipid metabolism, including fatty acid translocase, uncoupling protein-3, peroxisome proliferator-activated receptors (alpha, delta), and carnitine palmitoyl transferase-1, was increased in AT2R-deficient mice. In response to high-fat feeding, these mice were protected against obesity and obesity-related glucose intolerance, as assessed by glucose tolerance tests. Moreover, lipid oxidation assessed by indirect calorimetry was higher in AT2R-deficient mice than in wild-type mice, irrespective of the diet. This suggests that AT2R-dependent signaling exerts a direct or indirect negative control on lipid utilization in muscles. These data support the idea that AT2R-dependent Ang II signaling increases adipose cell mass and glucose intolerance and thus could participate to the deleterious effects of a high-fat diet.     

Renal hemodynamic effect of angiotensin II type 2 receptor

In the present study, the role of the angiotensin II type 2 receptor in the regulation of medullary blood flow in conscious Spontaneous Hypertensive Rats(SHR) was investigated. We tested the hypothesis that AT2 receptor activation may exert the opposite effects of AT1 receptors in terms of renal hemodynamics. Mean arterial pressure(MAP), daily sodium balance, cortical blood flow(CBF), and medullary blood flow(MBF) were measured over a 10-day protocol in several groups of rats in which optical fibers for laser-Doppler flowmetry had been implanted and which received the following drug combinations: the AT1 receptor antagonist CV11976(CV) alone and CV plus AT2 receptor antagonist PD123319 (PD). In the CV alone group, the renal interstitial administration of CV decreased MAP, caused sodium diuresis, and increased MBF significantly. In the CV plus PD group, the renal interstitial administration of PD prevented sustained hypotension, sodium diuresis, and increased medullary blood flow during CV administration. These data indicated that AT2 receptor activation leads to vasodilation in the renal medulla and an antihypertensive effect in SHR. AT2 receptors play an important role in the renal medullary blood flow.     

Differential kinetics of circulating angiotensin IV and II after treatment with angiotensin II type 1 receptor antagonist and their plasma levels in patients with chronic renal failure

BACKGROUND: Angiotensin II (Ang II) C-terminal hexapeptide (referred to as Ang IV) possesses the characteristics of a real hormone with specific receptors and biological effects. Clinical application of Ang II type 1 receptor (AT1-R) antagonists cause an increase in plasma Ang II level, which may result in enhanced production of Ang IV. PATIENTS AND METHODS: In this study, we measured plasma Ang IV and Ang II levels in patients with chronic renal failure (CRF), and also examined the changes in Ang IV and Ang II levels after administration of an ATI-R antagonist. RESULTS: Ang II and Ang IV levels in CRF patients untreated with hemodialysis (n = 16) were 15.8+/-3.6 and 6.0+/-1.1 pg/ml, respectively, which did not differ significantly from Ang II (20.6+/-2.4) and Ang IV levels (8.6+/-1.1) in normal controls (n = 23). The ratio of Ang IV to Ang II was 38%, similar to that in the controls (41%). Ang II or Ang IV levels in CRF patients treated with hemodialysis (n = 12) were also similar to the control values. Ang IV levels had a significant correlation with Ang II levels (r = 0.59). When hypertensive patients were treated with an AT1-R antagonist candesartan for 7 days, Ang II and Ang IV levels were increased 5.5- and 4.1-fold relative to the control levels, respectively. Ang II levels 28 and 56 days after treatment were significantly lower than those 7 days after treatment, whereas Ang IV levels did not differ significantly from those 7 days after treatment. Similar differential kinetics in Ang II and Ang IV levels after long-term (90 days) treatment with an AT1-R antagonist was also confirmed in experiments using rats. Significant decrease in blood pressure continued during long-term treatment with an AT1-R antagonist. CONCLUSION: These findings demonstrated that plasma Ang IV levels in patients with CRF did not differ significantly from those in normal subjects, and that treatment with an AT1-R antagonist caused marked increases in both Ang II and Ang IV levels. In contrast, during long-term treatment plasma Ang II levels were more rapidly decreased than Ang IV levels, suggesting longer-lasting enhancement of the action of Ang IV rather than that of Ang II after treatment with an AT1-R antagonist.     

Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats

Whether temporary angiotensin II (AngII) blockade at the prediabetic stage attenuates renal injury in type 2 diabetic OLETF rats later in life was investigated. OLETF rats were treated with an AT(1) receptor antagonist (olmesartan, 0.01% in food), angiotensin-converting enzyme inhibitor (temocapril, 0.01% in food), a combination of the two, or hydralazine (25 mg/kg per d) at the prediabetic stage (4 to 11 wk of age) and then monitored without further treatment until 50 wk of age. At 11 wk of age, blood glucose levels and urinary protein excretion (U(protein)V) were similar between OLETF and control LETO rats. However, OLETF rats showed higher kidney AngII contents and type IV collagen mRNA expression than LETO rats at this age. These decreased with olmesartan, temocapril, and a combination of these but not with hydralazine. At 50 wk of age, diabetic OLETF rats showed higher BP, U(protein)V, and intrarenal AngII levels than LETO rats. Temporary AngII blockade did not affect glucose metabolism or the development of hypertension in OLETF rats but significantly suppressed proteinuria and ameliorated glomerular injury. However, no parameters were affected by temporary hydralazine treatment. The present study demonstrated that intrarenal AngII and type IV collagen expression are already augmented long before diabetes becomes apparent in OLETF rats. Furthermore, temporary AngII blockade at the prediabetic stage attenuates the progression of renal injury in these animals. These data suggest that early AngII blockade could be an effective strategy for preventing the development of type 2 diabetic renal injury later in life.     

The role of angiotensin II type 1 receptor-activating antibodies in renal allograft vascular rejection

Acute rejection with vascular involvement remains a challenging problem in renal allotransplantation. Fibrinoid necrosis of the arteries with secondary thrombotic occlusions is C4d negative in 50% of cases and has the worst prognosis among all allograft vascular lesions. Nonhuman leukocyte antigen (HLA) non-complement-fixing antibodies reacting to artery-specific antigens have been speculated to be responsible for causing severe vascular injury. We recently reported the presence of agonistic antibodies against the angiotensin II type 1 receptor (AT₁R-AA) in 16 recipients of renal allografts who had severe vascular rejection and malignant hypertension but who did not have anti-HLA antibodies. AT₁R-AA stimulate AT₁R and induce mediators of inflammation and thrombosis. Removal of AT₁R-AA by plasmapheresis in combination with pharmacologic AT₁R blockade leads to improved renal function and graft survival in AT₁R-AA-positive patients. We have shown that the analysis of the subtle diagnostic and mechanistic differences may help to identify patients at particular risk and improve outcome of rejections with vascular pathology.     

2型糖尿病患者合并非糖尿病性肾损害的临床病理分析

目的：了解2型糖尿病合并非糖尿病性肾损害的临床病理特点。方法：总结分析29例2型糖尿病合并非糖尿病肾损害的临床资料、病理改变及治疗反应。结果：2型糖尿病或糖尿病肾病可以合并多种非糖尿病肾损害,以各种类型的原发性及继发性肾小球疾病为主。原发性肾小球疾病常见病理类型有轻度系膜增生性肾小球肾炎、膜性肾病、IgA肾病和微小病变。这些患者具有以下不同于典型糖尿病肾病的特点：（1）糖尿病病程短于5年;（2）大量蛋白尿或肾功能不全时血压正常;（3）急性肾功能衰竭;（4）血尿明显。大部分肾病水平蛋白尿患者经糖皮质激素或糖皮质激素联合细胞毒类药物治疗后可完全缓解.结论：（1）2型糖尿病合并肾损害不等于糖尿病肾病;（2）2型糖尿病可以合并各种非糖尿病性肾损害;（3）当2型糖尿病伴肾脏受累者具有上述不符合糖尿病肾病特征时,应尽早行肾活检明确诊断;（4）在充分考虑患者 的临床特点、病理改变、严格控制血糖及血压的情况下,糖皮质激素或糖皮质激素联合细胞毒类药物治疗是安全有效的,可以改变患者的预后。     

Angiotensin-converting enzyme inhibition but not angiotensin II receptor blockade regulates matrix metalloproteinase activity in patients with glomerulonephritis

Equivalent long-term effects on the kidney are attributed to angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB). Nevertheless, it is unknown to which degree effects of these compounds on individual inflammatory mediators, including matrix metalloproteinases (MMP), are comparable. On the basis of structural and functional differences, it was hypothesized that ACEI and ARB differentially regulate MMP activity. In a randomized, prospective crossover trial, the effect of an ACEI (fosinopril; 20 mg/d) and of an ARB (irbesartan; 150 mg/d) on MMP activity was evaluated. Ten hypertensive patients with glomerulonephritis and normal or mildly reduced creatinine clearance were studied. MMP activity and tissue inhibitors of metalloproteinase (TIMP) levels were analyzed in serum and urine: without therapy, with ACEI, with ARB, and with both agents combined. Treatment periods continued for 6 wk separated by periods of 4 wk each without therapy. Untreated patients with glomerulonephritis displayed distinctively higher serum levels of MMP-2 but much lower MMP-1/-8/-9 concentrations compared with healthy control subjects. Immunohistology of MMP-2 and MMP-9 in kidney biopsy specimen was accordingly. However, these patients excreted higher amounts of MMP-2 and MMP-9 in urine than healthy control subjects, possibly reflecting ongoing glomerular inflammation. In patients with glomerulonephritis, ACEI significantly reduced overall MMP serum activity to 25%, whereas ARB did not show any effect. Activities of MMP-1/-2/-8/-9 were also significantly inhibited by fosinopril but not by irbesartan. Levels of TIMP-1/-2 remained unaffected. In conclusion, ACEI and ARB differentially regulate MMP activity, which may ultimately have consequences in certain types of MMP-dependent glomerulonephritis.     

Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice

Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngII type 1a receptor gene-deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged prorenin receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a receptor gene-deficient mice. Only the prorenin receptor blockade with a short peptide of prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in AngII in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system-activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the receptor-associated prorenin that plays a pivotal role in diabetic nephropathy.     

Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes

We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to beta-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves beta-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined.     

Successful use of angiotensin II receptor antagonist (losartan) in a patient with scleroderma renal crisis

A 67-year-old man with a one-and-a half-year history of Raynaud's phenomenon was admitted to our hospital for progressive dyspnea occurring over the previous two weeks. Physical examination revealed a blood pressure of 200/124 mmHg, and slightly tight and smooth skin of the fingers, hands and forearms. Laboratory evaluation included serum creatinine of 5.42 mg/dl, plasma renin activity > 20 ng/ml/hr, and antinuclear antibody with a titer of 1 : 1,280. Renal biopsy was performed and the histopathological findings showed that some glomeruli exhibited ischemic retraction with wrinkling of the basement membranes, and that one arteriole exhibited significant intimal hyperplasia with luminal stenosis. These findings were compatible with scleroderma renal crisis (SRC). On the 5th day, serum creatinine had risen to 9.16 mg/dl, and he required temporary hemodialysis therapy. After the administration of captopril was started, his blood pressure fell to 160/86 mmHg and serum creatinine was reduced to 5.12 mg/dl. On the 9th day, he exhibited skin eruptions, and captopril was discontinued accordingly and temocapril started. Because of continued eruptions, temocapril was replaced by losartan. His blood pressure was controlled easily and his serum creatinine level reduced steadily. One year after the start of losartan, serum creatinine was 2.25 mg/dl and blood pressure was 130/82 mmHg. SRC is a life-threatening manifestation of systemic sclerosis. In the late 1970s, angiotensin converting enzyme (ACE) inhibitor was introduced and has dramatically improved the outcome in SRC patients. As ACE inhibitors act mainly on hyperreninemic renal vasoconstrictive hypertension in SRC, we would expect losartan, a selective antagonist of angiotensin receptor subtype 1, to be interchangeable with ACE inhibitors in SRC. In 1997, Caskey and colleagues reported the failure of losartan to control hypertension in a patient of SRC, and the reason has remained unclear. We report here, a case of SRC whose blood pressure was controlled successfully and his renal failure reversed by the administration of losartan.