RESUMEN
The (pro)renin receptor ((P)RR) is known to play an important role in the pathogenesis of vascular complications in diabetes mellitus and hypertension through its function in activating the local renin-angiotensin system. Recent studies have shown that the (P)RR is an accessory protein of the vacuolar H(+)-ATPase, suggesting a more fundamental and developmental function. In this study, smooth muscle cell-specific (P)RR/Atp6ap2 conditional knockout mice were generated. Smooth muscle cell-specific ablation of the (P)RR resulted in nonatherogenic sclerosis in the abdominal aorta. The deletion of the (P)RR did not affect ambulatory blood pressure levels. In cultured murine vascular smooth muscle cells (VSMCs), ablation of the (P)RR suppressed the expression of the Vo subunit c of the vacuolar H(+)-ATPase and impaired the cell recycling system, leading to autophagic cell death. In addition, loss of the (P)RR in VSMCs induced the expression of monocyte chemotactic protein-1 and interleukin-6 mRNAs. These results suggest that the (P)RR is essential for cell survival and downregulation of vascular inflammation in murine VSMCs through maintaining normal function of the vacuolar H(+)-ATPase.
Asunto(s)
Aorta Abdominal/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Receptores de Superficie Celular/metabolismo , ATPasas de Translocación de Protón Vacuolares/metabolismo , Animales , Supervivencia Celular , Células Cultivadas , Regulación hacia Abajo , Ratones , Ratones Noqueados , Receptores de Superficie Celular/genética , Renina/sangre , Sistema Renina-Angiotensina/fisiología , Receptor de ProreninaRESUMEN
The prorenin receptor is an accessory subunit of the vacuolar H(+)-ATPase, suggesting that it has fundamental functions beyond activation of the local renin-angiotensin system. Podocytes express the prorenin receptor, but its function in these cells is unknown. Here, podocyte-specific, conditional, prorenin receptor-knockout mice died of kidney failure and severe proteinuria within 4 weeks of birth. The podocytes of these mice exhibited foot process effacement with reduced and altered localization of the slit-diaphragm proteins nephrin and podocin. Furthermore, the podocytes contained numerous autophagic vacuoles, confirmed by enhanced accumulation of microtubule-associated protein 1 light chain 3-positive intracellular vesicles. Ablation of the prorenin receptor selectively suppressed expression of the V(0) c-subunit of the vacuolar H(+)-ATPase in podocytes, resulting in deacidification of intracellular vesicles. In conclusion, the prorenin receptor is important for the maintenance of normal podocyte structure and function.
Asunto(s)
Podocitos/fisiología , Podocitos/ultraestructura , Receptores de Superficie Celular/fisiología , Animales , Muerte Celular , Ratones , Receptor de ProreninaRESUMEN
The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-ß mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-ß mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.
Asunto(s)
Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/fisiopatología , Oligopéptidos/uso terapéutico , Renina/antagonistas & inhibidores , Renina/fisiología , Angiotensina II/antagonistas & inhibidores , Angiotensina II/sangre , Animales , Progresión de la Enfermedad , Hipertensión Renovascular/patología , Hipertensión Renovascular/fisiopatología , Enfermedades Renales/patología , Masculino , Ratas , Ratas Sprague-Dawley , Renina/sangre , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/sangreRESUMEN
High plasma prorenin levels predict the onset of microvascular complications, such as albuminuria/proteinuria,in diabetic patients. In diabetic rats with elevated plasma prorenin levels, treatment with HRP, which competitively inhibits the binding of prorenin to the (pro)renin receptor [(P)RR] as a decoy peptide, significantly prevented the development of albuminuria/proteinuria and glomerulosclerosis, suggesting that (P)RR-bound prorenin plays a significant role in the pathogenesis of diabetic nephropathy. Recently, the presence of (P)RR in podocytes, which represent one of the glomerular filtration barriers, has been reported. Although podocytes are subjected to both high glucose levels and mechanical stretching caused by glomerular hyperfiltration under diabetic conditions, the expression of (P)RR is reportedly regulated by high glucose levels in in vitro mesangial cells and the in vivo kidneys of diabetic rats, whereas mechanical stretching is up-regulated by (P)RR expression in human podocytes. In addition, prorenin treatment not only leads to the generation of intracellular angiotensin (Ang)II, but also activates the phosphorylation of ERK via (P)RR in a manner that acts independently of AngII in human podocytes. Thus, the upregulation of prorenin and (P)RR in podocytes as a result of glomerular hyperfiltration might play an important role in the development of albuminuria/proteinuria via the generation of intracellular AngII and the stimulation of (P)RR-dependent intracellular signals. Further inquiry regarding podocyte (P)RR intracellular signal transduction will be needed to develop a new therapeutic approach targeting podocyte (P)RR in patients with diabetic nephropathy.
Asunto(s)
Diabetes Mellitus/patología , Podocitos/metabolismo , Podocitos/patología , Renina/fisiología , Animales , Diabetes Mellitus/sangre , Diabetes Mellitus/metabolismo , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Humanos , Modelos Biológicos , Podocitos/fisiología , Pronóstico , Ratas , Renina/metabolismo , Renina/farmacología , Sistema Renina-Angiotensina/fisiología , Transducción de Señal/fisiologíaRESUMEN
Angiotensin receptor blockers (ARBs) are known to reduce the cardiovascular risk in hypertensive patients. This study was designed to examine the effect of an ARB candesartan on subclinical atherosclerosis assessed by cardio-ankle vascular index (CAVI) in comparison with calcium channel blockers (CCBs) alone in hypertensive patients with metabolic syndrome (MetS). A total of 53 consecutive hypertensive patients with MetS were randomly assigned to the candesartan group, in which candesartan was added on, or the CCBs group, in which CCBs were added on. Clinical and biological parameters were obtained before and after the 12-month treatment period. The primary measure of efficacy was the %change in CAVI. When treated with candesartan, but not CCBs, CAVI significantly decreased from 8.7 to 7.7 by 11%. Blood pressure (BP) significantly decreased with both treatments, but the differences between groups were not significant. The changes in other parameters remained unchanged in both the groups. Analysis of covariance found that both the BP reduction and the therapy difference contributed to the decrease in CAVI, but the BP reduction was not involved in the decrease in CAVI caused by the difference in the therapy. Candesartan may be a better antihypertensive drug than CCBs to improve subclinical atherosclerosis of patients with MetS.
Asunto(s)
Antihipertensivos/uso terapéutico , Bencimidazoles/uso terapéutico , Hipertensión/tratamiento farmacológico , Síndrome Metabólico/tratamiento farmacológico , Tetrazoles/uso terapéutico , Tobillo/irrigación sanguínea , Antihipertensivos/farmacología , Arterias/efectos de los fármacos , Arterias/fisiopatología , Bencimidazoles/farmacología , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Arterias Carótidas/diagnóstico por imagen , Femenino , Humanos , Hipertensión/fisiopatología , Riñón/fisiopatología , Masculino , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Monitoreo Ambulatorio , Péptido Natriurético Encefálico/sangre , Tetrazoles/farmacología , UltrasonografíaRESUMEN
Since renin inhibition interferes with the first and rate-limiting steps in the renin-angiotensin system, the renin step is a very attractive target for lowering blood pressure and minimizing target-organ damage. The newly developed direct renin inhibitor aliskiren has several attractive characteristics: it definitively reduces plasma renin activity among inhibitors of the renin-angiotensin system, is remarkably specific for human renin, exhibits a long half-life in plasma comparable to that of amlodipine, and has a high affinity for renal glomeruli and vasculature. Although these characteristics suggest the clinical usefulness and safety of aliskiren, several problems remain unsolved. Why does aliskiren have beneficial effects on the heart and kidneys of patients treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1-receptor blockers (ARBs)? Is the blood-pressure-lowering effect of aliskiren dependent on the plasma renin activity? Does aliskiren exert a possible adverse effect via (pro)renin receptor-dependent intracellular signals? Here, we review the characteristics and usefulness of aliskiren and discuss the current issues associated with this direct renin inhibitor.
Asunto(s)
Amidas/farmacología , Antihipertensivos/farmacología , Fumaratos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Renina/antagonistas & inhibidores , Amidas/farmacocinética , Antihipertensivos/farmacocinética , Fumaratos/farmacocinética , Semivida , HumanosRESUMEN
BACKGROUND/AIMS: This study was conducted to determine the effect of telmisartan on the cardio-ankle vascular index (CAVI), a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. METHODS: One hundred consecutive hypertensive patients were randomly assigned either to a group treated with calcium channel blocker (CCB)-based therapy or a group treated with telmisartan-based therapy. Clinical and biological parameters were then measured before and 12 months after the start of this study. RESULTS: CAVI, the logarithm of urinary albumin excretion, and BP were reduced significantly after telmisartan-based therapy. The decreases in 24-hour diastolic BP and daytime systolic BP associated with telmisartan-based therapy were significantly greater than those associated with CCB-based therapy. Both therapies significantly and similarly decreased the clinical BP, 24-hour systolic BP, daytime diastolic BP and serum levels of low-density lipoprotein cholesterol. No significant differences in the metabolic parameters were observed between the two therapies. CONCLUSION: Telmisartan-based therapy had beneficial effects on arterial stiffness assessed by CAVI, albuminuria, 24-hour BP and metabolism compared with CCB-based therapy. Since these markers are known to influence the future risk of cardiovascular events, telmisartan could be a useful drug for hypertensive patients.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bencimidazoles/administración & dosificación , Benzoatos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Hipertensión Renal/diagnóstico , Hipertensión Renal/tratamiento farmacológico , Adulto , Albuminuria/tratamiento farmacológico , Albuminuria/fisiopatología , Tobillo/irrigación sanguínea , Arterias/efectos de los fármacos , Arterias/fisiopatología , Determinación de la Presión Sanguínea/métodos , Bloqueadores de los Canales de Calcio/administración & dosificación , Femenino , Humanos , Hipertensión Renal/fisiopatología , Masculino , Persona de Mediana Edad , Modelos Cardiovasculares , Telmisartán , Resultado del TratamientoRESUMEN
To examine the involvement of (pro)renin receptor in the accelerated organ damage in streptozotocin-induced diabetic male SHRsp, the rats fed a high-salt diet were divided into 5 groups: a group treated with the vehicle, a group treated with 15 mg/kg/day of imidapril (ACEi), a group treated with 60 mg/kg/day of imidapril (High ACEi), a group treated with handle region peptide (HRP), and a group treated with both ACEi and HRP (ACEi+HRP). After 8 weeks, the arterial pressure was similar in the vehicle and HRP groups and decreased in the ACEi-treated groups. The renal angiotensin II content decreased similarly in the groups treated with ACEi and/or HRP. Urinary protein excretion also decreased in the ACEi, High ACEi, and HRP groups and significantly further decreased in the ACEi+HRP group. The heart weight of the ACEi+HRP group was significantly lower than that of any other groups, although the cardiac angiotensin II levels decreased similarly in the groups treated with ACEi and/or HRP. Thus, (pro)renin receptor contributes to the accelerated pathogenesis in the heart and kidneys of diabetic SHRsp.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Imidazolidinas/uso terapéutico , Receptores de Superficie Celular/antagonistas & inhibidores , Angiotensina II/metabolismo , Animales , Glucemia , Presión Sanguínea , Peso Corporal , Colágeno Tipo I/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Masculino , Tamaño de los Órganos , ARN Mensajero/genética , Ratas , Ratas Endogámicas SHR , Receptores de Superficie Celular/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta/genética , Receptor de ProreninaRESUMEN
RATIONALE: The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H(+)-ATPase (V-ATPase), implicating a non-RAS-related function of ATP6AP2. OBJECTIVE: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. METHODS AND RESULTS: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V(O) subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. CONCLUSIONS: Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non-RAS-related function that is essential for cell survival.
Asunto(s)
Miocitos Cardíacos/enzimología , Precursores de Proteínas/fisiología , Receptores de Superficie Celular/fisiología , Renina/fisiología , ATPasas de Translocación de Protón Vacuolares/metabolismo , Animales , Supervivencia Celular/genética , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/patología , Ratones , Ratones Noqueados , Miocitos Cardíacos/patología , Precursores de Proteínas/genética , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Renina/genética , ATPasas de Translocación de Protón Vacuolares/deficiencia , ATPasas de Translocación de Protón Vacuolares/fisiología , Receptor de ProreninaRESUMEN
BACKGROUND: A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes. METHODS: Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined. RESULTS: The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren. CONCLUSIONS: Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.
Asunto(s)
Amidas/farmacología , Angiotensina II/metabolismo , Fumaratos/farmacología , Podocitos/metabolismo , Receptores de Superficie Celular/efectos de los fármacos , Renina/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bencimidazoles/farmacología , Compuestos de Bifenilo , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Imidazolidinas/farmacología , Fosforilación/efectos de los fármacos , Podocitos/citología , Podocitos/efectos de los fármacos , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Receptores de Superficie Celular/fisiología , Renina/farmacología , Transducción de Señal/fisiología , Tetrazoles/farmacología , Receptor de ProreninaRESUMEN
1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high-sodium (8% NaCl) diet and heminephrectomy on PAC were examined. 2. Feeding of the high-sodium diet for 12 weeks similarly decreased PAC in TG and wild-type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high-sodium diet, but had no effect on PAC in WT rats fed a high-sodium diet. 3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high-sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not. 4. Nephrin and podocin mRNA levels, as determined by real-time quantitative reverse transcription-polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)-1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO-1 mRNA levels in TG rats. 5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.
Asunto(s)
Aldosterona/sangre , Enfermedades Renales/prevención & control , Antagonistas de Receptores de Mineralocorticoides , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Receptores de Superficie Celular/fisiología , Espironolactona/análogos & derivados , Animales , Eplerenona , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/farmacología , Nefrectomía , Ratas , Ratas Transgénicas , Receptores de Superficie Celular/genética , Cloruro de Sodio Dietético/administración & dosificación , Espironolactona/administración & dosificación , Espironolactona/farmacología , Espironolactona/uso terapéutico , Receptor de ProreninaRESUMEN
Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology.
Asunto(s)
Diabetes Mellitus/fisiopatología , Hipertensión/fisiopatología , Receptores de Superficie Celular/fisiología , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Humanos , Enfermedades Renales/fisiopatología , Ratones , Ratones Noqueados , Ratas , Ratas Endogámicas SHR , ATPasas de Translocación de Protón Vacuolares/fisiología , Receptor de ProreninaRESUMEN
This study was conducted to determine the effects of a tablet combining losartan/hydrochlorothiazide (L/HCTZ) in comparison with losartan alone in Japanese diabetic patients with hypertension. Thirty consecutive Japanese diabetic patients with hypertension were randomly assigned to group A, receiving losartan alone for the first 3 months, then L/HCTZ for the next 3 months, or group B, receiving L/HCTZ for the first 3 months, then losartan alone for the next 3 months. Clinical and biological parameters were obtained before, and 3 and 6 months after the start of this study. The decreases in systolic and diastolic blood pressure (BP) during treatment with L/HCTZ were significantly greater than in treatment with losartan alone. Both treatments significantly and similarly decreased urinary albumin excretion, the cardio-ankle vascular index (CAVI) and augmentation index (AI). There was no significant difference in metabolic change during both the mono- and combination pharmacotherapies. The tablet combining L/HCTZ significantly reduced systolic and diastolic BP compared with the losartan monotherapy, and offered benefits similar to losartan monotherapy for albuminuria, arterial stiffness assessed by the CAVI and AI, and metabolic effects. Thus, the L/HCTZ tablet could be a useful drug for Japanese diabetic patients with hypertension.
Asunto(s)
Antihipertensivos/administración & dosificación , Complicaciones de la Diabetes , Hidroclorotiazida/administración & dosificación , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Losartán/administración & dosificación , Adulto , Albuminuria/complicaciones , Aldosterona/sangre , Antihipertensivos/efectos adversos , Pueblo Asiatico , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Combinación de Medicamentos , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Losartán/efectos adversos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Renina/sangre , Comprimidos , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: A significant role of (pro)renin receptor in the pathogenesis of end-organ damage has been suggested only in animal studies. This study was conducted to examine the mRNA expression of (pro)renin receptor in human artery. METHODS: In 141 kidney failure patients, the mRNA was harvested from arterial fragments obtained during surgery constructing an arteriovenous access for hemodialysis therapy, and expression levels of (pro)renin receptor and other components of the renin-angiotensin system were determined. RESULTS: Arterial (pro)renin receptor expression was similar in diabetic and non-diabetic patients, although plasma prorenin levels were significantly higher in the diabetic patients than in the non-diabetic patients. The arterial (pro)renin receptor mRNA levels of the hypertensive patients, who had not been treated with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers, were significantly lower than those of the patients who had been treated with either drug. Multiple regression analyses showed a significant association with a large coefficient between the arterial mRNA level of the (pro)renin receptor and the arterial mRNA level of ACE; this significant association disappeared in patients who had been treated with either drug. CONCLUSION: (Pro)renin receptor may contribute to the generation of arterial angiotensin II in kidney failure patients.
Asunto(s)
Arterias/fisiología , Fallo Renal Crónico/genética , Fallo Renal Crónico/fisiopatología , Peptidil-Dipeptidasa A/genética , Receptores de Superficie Celular/genética , Anciano , Aldosterona/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Derivación Arteriovenosa Quirúrgica , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/fisiopatología , Femenino , Regulación de la Expresión Génica/fisiología , Humanos , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/genética , Hipertensión Renal/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , ARN Mensajero/metabolismo , Análisis de Regresión , Renina/sangre , Receptor de ProreninaRESUMEN
The binding of prorenin to the (pro)renin receptor triggers 2 major pathways: a nonproteolytic conformational change in prorenin to its active form (angiotensin II-dependent pathway) and an intracellular pathway via the (pro)renin receptor itself (angiotensin II-independent pathway). In diabetic animals, an increased plasma prorenin level not only causes the generation of angiotensin II via the angiotensin II-dependent pathway, it also stimulates the transliteration receptors own intracellular signaling pathway in a manner that is independent of the generated angiotensin II. Thus, the administration of a "handle" region peptide (HRP), which acts as a decoy peptide and competitively inhibits the binding of prorenin to the (pro)renin receptor, has a beneficial effect in the kidneys of diabetic animals with low plasma renin levels. However, the benefits of HRP are slightly reduced in animal models of essential hypertension with relatively high plasma renin levels, and these benefits disappear altogether in animal models of hypertension with extremely high plasma renin levels. Thus, in the kidneys of animal models of diabetes and/or hypertension, both renin and prorenin competitively bind to the (pro)renin receptor and contribute to the pathophysiology of nephropathy. Consequently, renin, prorenin and the (pro) renin receptor may be important therapeutic targets for the prevention and regression of nephropathy in patients with diabetes and/or hypertension.
Asunto(s)
Enfermedades Renales/etiología , Renina/fisiología , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/etiología , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Isquemia/fisiopatología , Riñón/irrigación sanguínea , Receptores de Superficie Celular/antagonistas & inhibidores , Sistema Renina-Angiotensina/fisiología , Receptor de ProreninaRESUMEN
Hypertension frequently requires combination therapy to attain efficient control to prevent cardiovascular diseases effectively. This study was conducted to determine which add-on treatment is better, namely calcium channel blockers or diuretics, in improving vascular damage. In 70 nondiabetic chronic kidney disease stage 1/2 patients who had been already treated with angiotensin II type 1 receptor blocker valsartan for at least 12 months, amlodipine or hydrochlorothiazide was added to their existing medication. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE), and 24-hour ambulatory blood pressure (BP) were determined before and 12 months after the start of add-on treatments. Add-on amlodipine and add-on hydrochlorothiazide significantly and similarly decreased 24-hour ambulatory BP by 18 and 19 mm Hg, respectively, PWV by 206 and 184 cm/s, respectively, and UAE, but did not change the IMT. The decreases in BP significantly contributed to the decreases in PWV and UAE and suggested that the decrease in serum cholesterol level brought about by add-on amlodipine also contributed to the decrease in UAE. These results suggest that 12 months of add-on treatment with either amlodipine or hydrochlorothiazide could have beneficial effects in nondiabetic chronic kidney disease stage 1/2 patients already being treated with valsartan.
Asunto(s)
Amlodipino/administración & dosificación , Hipertensión/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Tetrazoles/administración & dosificación , Tiazidas/administración & dosificación , Valina/análogos & derivados , Adulto , Albuminuria , Antihipertensivos , Presión Sanguínea/efectos de los fármacos , Monitoreo Ambulatorio de la Presión Arterial , Bloqueadores de los Canales de Calcio , Arterias Carótidas/patología , Diuréticos , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/tratamiento farmacológico , Valina/administración & dosificación , ValsartánRESUMEN
Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II-independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.
Asunto(s)
Descubrimiento de Drogas/métodos , Fallo Renal Crónico/tratamiento farmacológico , Péptidos/uso terapéutico , Receptores de Superficie Celular/antagonistas & inhibidores , Animales , Humanos , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/prevención & control , Modelos Biológicos , Péptidos/síntesis química , Péptidos/farmacología , Receptores de Superficie Celular/fisiología , Receptor de ProreninaRESUMEN
High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between these factors has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in the kidneys include the mesangium and podocytes. The binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of the conversion of prorenin to the active form of prorenin through a conformational change, and the angiotensin II-independent, (pro)renin-receptor-dependent intracellular mitogen-activated protein kinase pathway. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes, the handle region peptide, which binds to the receptor and competitively inhibits prorenin from binding to the receptor, was administered to rats with streptozotocin-induced type I diabetes and to a model of type II diabetes, db/db mice. The handle region peptide significantly inhibited the development of end-organ damage in these diabetic animals, and had a greater benefit than angiotensin-converting enzyme inhibitors in diabetic angiotensin II-type 1a-receptor-deficient mice. In addition, the infusion of the handle region peptide in animals with streptozotocin-induced type I diabetes significantly regressed the nephropathy that had already occurred. These results suggest that prorenin and the (pro)renin receptor play a pivotal role in the pathophysiology of diabetic nephropathy. Receptor-bound prorenin may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in patients with diabetes.
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Nefropatías Diabéticas/etiología , Receptores de Superficie Celular/fisiología , Renina/fisiología , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Humanos , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/metabolismo , Renina/antagonistas & inhibidores , Renina/metabolismo , Receptor de ProreninaRESUMEN
BACKGROUND: Patients with kidney failure treated with hemodialysis have a high incidence of cardiovascular diseases caused by accelerated arteriosclerosis. However, accurate evaluation of the extent of arteriosclerosis is difficult. This study sought to compare the strength of predictions of arterial fibrosis by using a new parameter, the cardio-ankle vascular index (CAVI), versus pulse wave velocity (PWV) in patients with kidney failure treated with hemodialysis. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 103 patients with kidney failure undergoing surgical construction of an arteriovenous access for hemodialysis therapy. INDEX TEST: CAVI and PWV. REFERENCE TEST: Arterial fibrosis, evaluated by using Masson trichrome stain on part of the brachial artery obtained during surgery, expressed as percentage of fibrosis of the layer of vascular smooth muscle cells. RESULTS: Median percentage of arterial stiffness was 52.85%. Mean PWV and CAVI were 18.3 +/- 5.6 (SD) m/s and 9.9 +/- 2.6, respectively. Multivariate regression analysis showed that arterial fibrosis was significantly associated with older age (0.247%/y; 95% confidence interval, 0.013 to 0.482) and CAVI (6.117%/unit; 95% confidence interval, 4.764 to 4.740), but not with systolic blood pressure (0.039%/mm Hg; 95% confidence interval, -0.076 to 0.153) or PWV (-0.044%/m/s; 95% confidence interval, -0.646 to 0.558). The area under the receiver operating characteristic curve to predict greater than median percentage of arterial stiffness was 0.892 for CAVI and 0.779 for PWV (P = 0.006). LIMITATION: It is unclear whether arterial fibrosis of the brachial artery evaluated by using CAVI is applicable for arteriosclerosis of other arterial districts, and clinical outcomes were not evaluated in this study. CONCLUSION: CAVI reflects the histological arterial fibrosis of hemodialysis patients and is a useful clinical marker for evaluating arterial stiffness in these patients.
Asunto(s)
Arterias/patología , Pulso Arterial , Diálisis Renal , Insuficiencia Renal/complicaciones , Insuficiencia Renal/fisiopatología , Anciano , Tobillo , Velocidad del Flujo Sanguíneo , Femenino , Fibrosis/diagnóstico , Fibrosis/etiología , Fibrosis/fisiopatología , Humanos , Masculino , Análisis MultivarianteRESUMEN
(Pro)renin receptor-bound prorenin not only causes the generation of angiotensin II via the nonproteolytic activation of prorenin, it also activates the receptor's own intracellular signaling pathways independent of the generated angiotensin II. Within the kidneys, the (pro)renin receptor is not only present in the glomerular mesangium, it is also abundant in podocytes, which play an important role in the maintenance of the glomerular filtration barrier. Recent in vivo studies have demonstrated that the overexpression of the (pro)renin receptor to a degree similar to that observed in hypertensive rat kidneys leads to slowly progressive nephropathy with proteinuria. In addition, the handle region peptide, which acts as a decoy peptide and competitively inhibits the binding of prorenin to the receptor, is more beneficial than an angiotensin-converting enzyme inhibitor with regard to alleviating proteinuria and glomerulosclerosis in experimental animal models of diabetes and essential hypertension. Thus, the (pro)renin receptor may be upregulated in podocytes under hypertensive conditions and may contribute to the breakdown of the glomerular filtration barrier.