RESUMO
Recently we demonstrated that increased renal (Pro)renin receptor (PRR) expression in diabetes contributes to development of diabetic kidney disease. However, the exact mechanisms involving PRR activity and diabetic kidney dysfunction are unknown. We hypothesized that PRR is localized in renal mitochondria and contributes to renal fibrosis and apoptosis through oxidative stress-induced mitochondria dysfunction. Controls and streptozotocin-induced diabetic C57BL/6 mice were injected with scramble shRNA and PRR shRNA and followed for a period of eight weeks. At the end of study, diabetic mice showed increased expressions of PRR and NOX4 in both total kidney tissue and renal mitochondria fraction. In addition, renal mitochondria of diabetic mice showed reduced protein expression and activity of SOD2 and ATP production and increased UCP2 expression. In diabetic kidney, there was upregulation in the expressions of caspase3, phos-Foxo3a, phos-NF-κB, fibronectin, and collagen IV and reduced expressions of Sirt1 and total-FOXO3a. Renal immunostaining revealed increased deposition of PRR, collagen and fibronectin in diabetic kidney. In diabetic mice, PRR knockdown decreased urine albumin to creatinine ratio and the renal expressions of PRR, NOX4, UCP2, caspase3, phos-FOXO3a, phos-NF-κB, collagen, and fibronectin, while increased the renal mitochondria expression and activity of SOD2, ATP production, and the renal expressions of Sirt1 and total-FOXO3a. In conclusion, increased expression of PRR localized in renal mitochondria and diabetic kidney induced mitochondria dysfunction, and enhanced renal apoptosis and fibrosis in diabetes by upregulation of mitochondria NOX4/SOD2/UCP2 signaling pathway.
Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/patologia , Rim/patologia , Mitocôndrias/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Receptores de Superfície Celular/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/genética , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/etiologia , Fibrose , Técnicas de Silenciamento de Genes , Rim/citologia , Masculino , Camundongos , Mitocôndrias/patologia , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/genética , ATPases Translocadoras de Prótons/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/metabolismo , Receptores de Superfície Celular/genética , Renina/metabolismo , Transdução de Sinais/genética , Estreptozocina/toxicidade , Superóxido Dismutase/metabolismo , Proteína Desacopladora 2/metabolismo , Regulação para CimaRESUMO
We hypothesized that direct AT2R stimulation improves albuminuria in diabetes by preventing renal inflammation and improving oxidative stress. Normoglycemic controls (NCs) and streptozotocin-induced diabetes Sprague-Dawley rats (DM) were treated for 4 weeks with vehicle (V) or the AT2R agonist Compound 21 (C21). At the end of study, we evaluated blood pressure, urinary albumin to creatinine ratio (UACR), renal interstitial fluid (RIF) levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nitric oxide (NO), cGMP, and 8-isoprostane, and renal expression of TNF-α, IL-6, and AT2R. There were no significant differences in blood pressure between different treatments. DM rats demonstrated increased UACR, RIF TNF-α, IL-6 and 8-isoprostane, and messenger RNA (mRNA) for TNF-α and IL-6. DM rats also had reduced RIF NO and cGMP. C21 treatment of DM rats limited the increase in UACR, normalized RIF TNF-α, IL-6 and 8-isoprostane, and in mRNA for TNF-α and IL-6, and increased RIF NO and cGMP. In NC rats, C21 treatment did not change these parameters. AT2R mRNA and protein expressions increased in DM rats compared with NC but were not influenced by C21 treatment. We conclude that direct AT2R stimulation in diabetic rats improves diabetic albuminuria through the prevention of renal inflammation and improved production of NO and cGMP.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Inflamação , Rim , Receptor Tipo 2 de Angiotensina/agonistas , Animais , GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Although angiotensin II subtype-2 receptor (AT2R) was discovered over 2 decades ago, its contribution to physiology and pathophysiology is not fully elucidated. Current knowledge suggests that under normal physiologic conditions, AT2R counterbalances the effects of angiotensin II subtype-1 receptor (AT1R). A major obstacle for AT2R investigations was the lack of specific agonists. Most of the earlier AT2R studies were performed using the peptidic agonist, CG42112A, or the nonpeptidic antagonist PD123319. CGP42112A is nonspecific for AT2R and in higher concentrations can bind to AT1R. Recently, the development of specific nonpeptidic AT2R agonists boosted the efforts in identifying the therapeutic potentials for AT2R stimulation. Unlike AT1R, AT2R is involved in vasodilation by the release of bradykinin and nitric oxide, anti-inflammation, and healing from injury. Interestingly, the vasodilatory effects of AT2R stimulation were not associated with significant reduction in blood pressure. In the kidney, AT2R stimulation produced natriuresis, increased renal blood flow, and reduced tissue inflammation. In animal studies, enhanced AT2R function led to reduction of cardiac inflammation and fibrosis, and reduced the size of the infarcted area. Similarly, AT2R stimulation demonstrated protective effects in vasculature and brain.
Assuntos
Encéfalo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Desenho de Fármacos , Rim/efeitos dos fármacos , Terapia de Alvo Molecular , Receptor Tipo 2 de Angiotensina/agonistas , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Fármacos Cardiovasculares/farmacologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , Sistema Cardiovascular/fisiopatologia , Fibrose , Humanos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Aldosterone is increased in diabetes and contributes to the development of diabetic nephropathy. The authors hypothesized that reduction in aldosterone production in diabetes by amlodipine or aliskiren improves diabetic kidney disease by attenuating renal oxidative stress and fibrosis. Normoglycemic and streptozotocin-induced diabetic Sprague-Dawley rats were given vehicle, amlodipine, or aliskiren alone and combined for 6 weeks. At the end of study, we evaluated blood pressure (BP), 24-hour urinary sodium (UNaV) and aldosterone excretion rates, renal interstitial fluid (RIF) levels of nitric oxide (NO), cyclic guanosine 3',5'-monophosphate (cGMP), and 8-isoprostane, and renal morphology. BP was not significantly different between any of experimental groups. UNaV increased in diabetic animals and was not affected by different treatments. Urinary aldosterone excretion increased in diabetic rats receiving vehicle and decreased with amlodipine and aliskiren alone or combined. RIF NO and cGMP levels were reduced in vehicle-treated diabetic rats and increased with amlodipine or aliskiren given alone and combined. RIF 8-isoprostane levels and renal immunostaining for periodic acid-Schiff and fibronectin were increased in vehicle-treated diabetic rats and decreased with aliskiren alone or combined with amlodipine. The authors conclude that inhibition of aldosterone by amlodipine or aliskiren ameliorates diabetes induced renal injury via improvement of NO-cGMP pathway and reduction in oxidative stress and fibrosis, independent of BP changes.
Assuntos
Aldosterona/metabolismo , Amidas/farmacologia , Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Fumaratos/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Glicemia/metabolismo , Pressão Sanguínea , GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Regulação para Baixo , Fibronectinas/metabolismo , Fibrose , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Natriurese , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Effects of low salt (LS) on (pro)renin receptor (PRR) expression are not well established. We hypothesized that LS enhances renal PRR expression via the cGMP-protein kinase G (PKG) signaling pathway. Sprague-Dawley rats were fed a normal-salt (NS) or LS diet associated with intrarenal cortical administration of vehicle (V), the nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (l-NAME), the NO donor S-nitroso-N-acetyl-dl-penicillamine (SNAP), the cGMP analog 8-bromoguanosine (8-Br)-cGMP, the guanylyl cyclase inhibitor 1H-[1, 2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), or a PKG inhibitor (PKGi) for 6 days via osmotic minipump. We evaluated the effects of each treatment on renal interstitial fluid (RIF) levels of nitrate/nitrite and cGMP and renal PRR expression. There were no significant changes in blood pressure with any of the treatments. Urinary sodium excretion was significantly lower in rats given a LS diet. Compared with NS + V, RIF nitrate/nitrite and cGMP levels increased in LS + V rats. In NS groups, RIF nitrate/nitrite and cGMP levels did not change with l-NAME, ODQ, or PKGi and increased in response to SNAP. 8-Br-cGMP increased RIF cGMP but not RIF nitrate/nitrite. In LS groups, RIF nitrate/nitrite decreased with l-NAME and did not change with ODQ or PKGi whereas RIF cGMP decreased with l-NAME, ODQ, and PKGi. PRR mRNA and protein increased in LS + V. In NS rats, PRR mRNA and protein increased in response to 8-Br-GMP and were not affected by any of other treatments. In LS rats, PRR mRNA and protein decreased significantly in response to l-NAME, ODQ, and PKGi. We conclude that LS intake enhances renal expression of PRR via cGMP-PKG signaling pathway.
Assuntos
Dieta Hipossódica , Rim/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/fisiologia , Animais , Pressão Sanguínea/fisiologia , GMP Cíclico/antagonistas & inibidores , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Rim/efeitos dos fármacos , Masculino , Modelos Animais , NG-Nitroarginina Metil Éster/farmacologia , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Pró-ReninaRESUMO
We hypothesized that compared with hydrochlorothiazide (HCTZ), the renin inhibitor aliskiren (ALISK) or amlodipine (AMLO) and their combination reduce albuminuria via reduction in renal inflammation, independent of blood pressure (BP) changes. We studied normal and streptozotocin-induced diabetic (DM) Sprague-Dawley rats treated for 6 weeks with vehicle, ALISK, HCTZ, or AMLO individually and combined and evaluated the effects of treatments on BP, urine albumin to creatinine ratio, renal interstitial fluid levels of angiotensin II, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) and renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B. There were no differences in BP between treatments. Only ALISK and its combinations reduced renal interstitial fluid angiotensin II. Urine albumin to creatinine ratio increased in DM rats and decreased with ALISK alone or combined with HCTZ or AMLO. HCTZ or AMLO individually and combined did not influence urine albumin to creatinine ratio. Renal interstitial fluid TNF-α and IL-6, and the renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B were increased in DM rats. These renal inflammatory markers were reduced only with ALISK or AMLO individually or combined with other treatments. We conclude that ALISK alone and combined with HCTZ or AMLO reduced albuminuria in diabetes via reduction in renal inflammation, independent of BP changes.
Assuntos
Albuminúria/tratamento farmacológico , Amidas/farmacologia , Anlodipino/farmacologia , Fumaratos/farmacologia , Hidroclorotiazida/farmacologia , Amidas/administração & dosagem , Anlodipino/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Quimioterapia Combinada , Fumaratos/administração & dosagem , Hidroclorotiazida/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Rim , Masculino , Ratos , Ratos Sprague-Dawley , Renina/antagonistas & inibidores , EstreptozocinaRESUMO
1. Transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF) are expressed in renal glomeruli, and contribute to the development of diabetic nephropathy. Recently, we showed that (pro)renin receptor (PRR) is upregulated in the kidneys of the streptozocin (STZ)-induced diabetes rat model. We hypothesized that in the presence of hyperglycaemia, increased renal PRR expression contributes to enhanced TGF-ß1-CTGF signalling activity, leading to the development of diabetic kidney disease. 2. In vivo and in vitro studies were carried out in Sprague-Dawley rats and rat mesangial cells (RMC). PRR blockade was achieved in vivo by treating STZ induced diabetes rats with the handle region peptide (HRP) of prorenin and in vitro by HRP or PRR siRNA in RMC. Angiotensin AT1 receptor blockade was achieved by valsartan treatment. 3. Results showed that expression of PRR, TGF-ß1 and CTGF were upregulated in diabetic kidneys and RMC exposed to high glucose. Glucose exposure also induced PRR phosphorylation, a process that was inhibited by HRP, valsartan or PRR siRNA. HRP and valsartan significantly attenuated renal TGF-ß1 and CTGF expression in diabetic animals and high glucose treated RMC. Similar results were observed in high glucose exposed RMC in response to PRR siRNA. TGF-ß receptor blockade decreased CTGF expression in RMC. Combined administration of valsartan and PRR siRNA showed further reduction of TGF-ß1 and CTGF expression in RMC. 4. In conclusion, PRR contributes to kidney disease in diabetes through an enhanced TGF-ß1-CTGF signalling cascade.
Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Nefropatias Diabéticas/metabolismo , Receptores de Superfície Celular/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Fator de Crescimento do Tecido Conjuntivo/genética , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/genética , Glucose/metabolismo , Glucose/farmacologia , Hiperglicemia/metabolismo , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Oligopeptídeos/genética , Oligopeptídeos/farmacologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Transdução de Sinais/efeitos dos fármacos , Tetrazóis/farmacologia , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/genética , Regulação para Cima , Valina/análogos & derivados , Valina/farmacologia , Valsartana , Receptor de Pró-ReninaRESUMO
Angiotensin II type 2 receptor (AT2R) counteracts most effects of angiotensin II type 1 receptor (AT(1)R). We hypothesized that direct AT2R stimulation reduces renal production of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and transforming growth factor-ß1 (TGF-ß1) and enhances the production of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) in the clipped kidney of 2-kidney, 1-clip (2K1C) hypertension rat model. We used Sprague-Dawley rats to evaluate changes in renal interstitial fluid recovery levels of TNF-α, IL-6, NO, and cGMP; renal expression of AT1R, AT2R, TGF-ß1, TNF-α, and IL-6 in sham and 2K1C rats treated for 4 days with vehicle, AT2R agonist compound 21 (C21), or AT2R antagonist PD123319 (PD), alone and combined (n=6, each group). Systolic blood pressure increased significantly in 2K1C and was not influenced by any treatment. Clipped kidneys showed significant increases in renal expression of AT1R, AT2R, TNF-α, IL-6, TGF-ß1 and decreases in NO and cGMP levels. These factors were not influenced by PD treatment. In contrast, C21 caused significant decrease in renal TNF-α, IL-6, TGF-ß1 and an increase in NO and cGMP levels. Combined C21 and PD treatment partially reversed the observed C21 effects. Compared to sham, there were no significant changes in TNF-α, IL-6, TGF-ß1, NO, or cGMP in the nonclipped kidneys of 2K1C animals. We conclude that direct AT2R stimulation reduces early renal inflammatory responses and improves production of NO and cGMP in renovascular hypertension independent of blood pressure reduction.
Assuntos
Hipertensão Renovascular/metabolismo , Inflamação/metabolismo , Rim/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea , Western Blotting , Peso Corporal , GMP Cíclico/metabolismo , Expressão Gênica , Hipertensão Renovascular/genética , Hipertensão Renovascular/fisiopatologia , Imidazóis/farmacologia , Inflamação/genética , Inflamação/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Óxido Nítrico/metabolismo , Tamanho do Órgão , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
1. (Pro)renin receptor (PRR) binding to renin or prorenin mediates angiotensin (Ang) II-dependent and -independent effects. Expression of the PRR is increased in kidneys of diabetic rats, but its role in diabetic nephropathy is unknown. In the present study, we investigated the contribution of the PRR to the development of diabetic nephropathy through enhancement of renal production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta. 2. Normoglycaemic control and streptozotocin-diabetic Sprague-Dawley rats were used in the study. The urine albumin : creatinine ratio (UACR), renal interstitial fluid (RIF) levels of AngII, TNF-alpha and IL-1beta and renal expression of TNF-alpha and IL-1beta were evaluated in control, untreated diabetic and diabetic rats treated with either a PRR blocker (PRRB; 0.2 mg/kg per day NH3-RILLKKMPSV-COOH), the AT(1) receptor antagonist valsartan (2 mg/kg per day) or combined therapy, administered directly into the renal cortical interstitium for 14 days via osmotic minipumps. 3. Compared with values in normoglycaemic control rats, UACR and RIF AngII, TNF-alpha and IL-1beta were significantly higher in untreated diabetic rats. Treatment of diabetic rats with the PRRB or valsartan alone and in combination significantly reduced UACR and RIF TNF-alpha and IL-1beta levels. Renal expression of TNF-alpha and IL-1beta was higher in untreated diabetic rats than in control rats, but was reduced significantly following treatment with PRRB or valsartan alone and in combination. Renal PRR expression was increased in untreated and PRRB-treated diabetic rats and reduced in rats receiving valsartan alone or combination therapy. The PRRB had no effect on RIF AngII levels, whereas valsartan alone and in combination with the PRRB significantly increased AngII levels. 4. In conclusion, the PRR is involved in the development and progression of kidney disease in diabetes by enhancing renal production of the inflammatory cytokines TNF-alpha and IL-1beta, independent of renal AngII effects.
Assuntos
Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Rim/metabolismo , Rim/patologia , Receptores de Superfície Celular/fisiologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Progressão da Doença , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/biossíntese , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/fisiologia , Receptor de Pró-ReninaRESUMO
Peroxynitrite (ONOO(-)) is formed endogenously by the reaction of nitric oxide (NO) and superoxide (O(2)(-)). To examine the hypothesis that OONO(-) cause renal vasodilation at low concentrations but cause vasoconstriction at higher concentrations, we examined renal responses to intra-arterial infusion of incremental doses of OONO(-) (10, 20, and 40 microg.kg(-1).min(-1); 45 min each) in anesthetized rats. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearance. In control rats (n = 6), low dose (10 microg.kg(-1).min(-1)) of OONO(-) increased RBF by 10 +/- 3% and GFR by 15 +/- 5%. The higher doses (20 and 40 microg.kg(-1).min(-1)) mostly reversed these responses which were -7 +/- 4 and -27 +/- 7% (P < 0.05) in RBF and -0.1 +/- 4.8 and -14 +/- 12% in GFR, respectively. There were no appreciable changes in urine flow (V) and sodium excretion (U(Na)V) during OONO(-) infusion. However, in rats pretreated with NO synthase (NOS) inhibitor, l-NAME (50 microg.kg(-1).min(-1); n = 5), these doses of ONOO(-) significantly reduced RBF (-26 +/- 7, -27 +/- 6, and -44 +/- 3%) and GFR (-21 +/- 6, -25 +/- 8, and -32 +/- 12%) with variable increases in V or U(Na)V. Long-term infusion of OONO(-) (10 microg.kg(-1).min(-1) for 75 min) in another set of control rats (n = 5) also showed similar vasodilator and hyperfiltration responses. These data indicate that ONOO(-) acts as an oxidant at high concentration but provides renoprotective function at low concentration that depends on intact NOS activity.
Assuntos
Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/efeitos dos fármacos , Ácido Peroxinitroso/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Taxa de Filtração Glomerular/fisiologia , Infusões Intra-Arteriais , Rim/irrigação sanguínea , Rim/fisiologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ácido Peroxinitroso/administração & dosagem , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/fisiologia , Inconsciência , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
We have previously shown that salt excess has adverse cardiac effects in spontaneously hypertensive rats (SHR), independent of its increased arterial pressure; however, the renal effects have not been reported. In the present study we evaluated the role of three levels of salt loading in SHR on renal function, systemic and renal hemodynamics, and glomerular dynamics. At 8 wk of age, rats were given a 4% (n = 11), 6% (n = 9), or 8% (n = 11) salt-load diet for the ensuing 8 wk; control rats (n = 11) received standard chow (0.6% NaCl). Rats had weekly 24-h proteinuria and albuminuria quantified. At the end of salt loading, all rats had systemic and renal hemodynamics measured; glomerular dynamics were specially studied by renal micropuncture in the control, 4% and 6% salt-loaded rats. Proteinuria and albuminuria progressively increased by the second week of salt loading in the 6% and 8% salt-loaded rats. Mean arterial pressure increased minimally, and glomerular filtration rate decreased in all salt-loaded rats. The 6% and 8% salt-loaded rats demonstrated decreased renal plasma flow and increased renal vascular resistance and serum creatinine concentration. Furthermore, 4% and 6% salt-loaded rats had diminished single-nephron plasma flow and increased afferent and efferent arteriolar resistances; glomerular hydrostatic pressure also increased in the 6% salt-loaded rats. In conclusion, dietary salt loading as low as 4% dramatically deteriorated renal function, renal hemodynamics, and glomerular dynamics in SHR independent of a minimal further increase in arterial pressure. These findings support the concept of a strong independent causal relationship between salt excess and cardiovascular and renal injury.
Assuntos
Albuminúria/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Rim/efeitos dos fármacos , Proteinúria/fisiopatologia , Circulação Renal/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Albuminúria/sangue , Albuminúria/etiologia , Albuminúria/patologia , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Relação Dose-Resposta a Droga , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/irrigação sanguínea , Rim/patologia , Testes de Função Renal , Masculino , Nefroesclerose/etiologia , Nefroesclerose/fisiopatologia , Tamanho do Órgão/efeitos dos fármacos , Proteinúria/sangue , Proteinúria/etiologia , Proteinúria/patologia , Ratos , Ratos Endogâmicos SHR , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: Hypertension involves the entire cardiovascular system, and hypertensive vascular disease may promote and exacerbate cardiac and renal dysfunction. We discuss the coexistence of cardiorenal disease as a manifestation of vascular involvement in hypertension, and the relationship of biomarkers of renal vascular involvement in hypertension with cardiovascular endpoints. RECENT FINDINGS: Markers of renal dysfunction, especially microalbuminuria, have been considered recently as potent predictors of cardiovascular morbidity and mortality in all explored populations, including hypertensive individuals. Microalbuminuria, per se, is related to vascular injury and to the increased glomerular permeability of albumin as a direct manifestation of renal vascular involvement in hypertension, a systemic vascular disease. Left ventricular hypertrophy in hypertension develops even before proteinuria or impairment of renal function. Factors including anemia, inflammation and hyperuricemia are either induced or exacerbated by renal vascular disease, and each of these may exert additional influence in determining the increased incidence of cardiovascular events with progressive renal dysfunction. SUMMARY: The development and progression of vascular disease is the primary determinant in the progressive cardiac and renal dysfunction observed in hypertension and, therefore, is the underlying mechanism of the overall clinical manifestations of cardiorenal disease. Commonly used biomarkers of renal and vascular function are important tools for determination of the progression and, hence, management of hypertensive disease and its complications.
Assuntos
Hipertensão/complicações , Hipertensão/fisiopatologia , Insuficiência Renal/etiologia , Insuficiência Renal/fisiopatologia , Albuminúria/etiologia , Biomarcadores/sangue , Biomarcadores/urina , Proteína C-Reativa/metabolismo , Progressão da Doença , Eritropoetina/sangue , Taxa de Filtração Glomerular , Humanos , Hipertensão/sangue , Hiperuricemia/etiologia , Peptídeo Natriurético Encefálico/metabolismo , Insuficiência Renal/sangue , Insuficiência Renal/complicações , Ácido Úrico/sangueRESUMO
BACKGROUND: Aldosterone has been implicated as a potential mediator of cardiac and vascular damage in a variety of disorders. This study examined the role of aldosterone and its interplay with the renin-angiotensin system in the pathogenesis of hypertension. To this end, the effects of the aldosterone antagonist eplerenone and the angiotensin converting enzyme inhibitor lisinopril on cardiovascular mass, myocardial collagen, and coronary circulation were examined in spontaneously hypertensive rats. METHODS: Male, 22-week-old rats were randomly divided into 4 groups (12 in each). The control group received no treatment, the second group was given eplerenone (100 mg/kg/day), the third received lisinopril (3 mg/kg/day), and the fourth was given eplerenone and lisinopril. After 12 weeks of respective treatments, systemic and regional hemodynamics and cardiovascular mass indexes were measured in conscious instrumented rats. RESULTS: Eplerenone decreased arterial pressure but did not affect left ventricular mass or hydroxyproline concentration (an estimate of collagen). It did, however, reduce minimal coronary vascular resistance and increased coronary flow reserve. Lisinopril decreased arterial pressure and ventricular mass but did not affect regional hemodynamics. The combination therapy produced synergistic effects. CONCLUSION: Aldosterone antagonism improved coronary and systemic hemodynamics in adult spontaneously hypertensive rats but did not affect cardiovascular mass indexes. The finding that lisinopril and eplerenone decreased arterial pressure to the same extent but had different cardiovascular effects suggested that these effects might be pressure independent.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Espironolactona/análogos & derivados , Animais , Circulação Coronária/efeitos dos fármacos , Eplerenona , Hipertensão/fisiopatologia , Lisinopril/farmacologia , Masculino , Ratos , Ratos Endogâmicos SHR , Espironolactona/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
The renal and glomerular dynamic effects of combining thiazide and angiotensin antagonists have not been reported. The present study was designed to examine the effects of hydrochlorothiazide (HCTZ) alone or in combination with an angiotensin-converting enzyme inhibitor or ANG II type 1-receptor blocker on renal hemodynamics, glomerular dynamics, renal function, and renal histopathology in the N(omega)-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (l-NAME/SHR) model. HCTZ (80 mg x kg(-1) x day(-1)) alone or in combination with enalapril (30 mg x kg(-1) x day(-1)) or losartan (30 mg x kg(-1) x day(-1)) or enalapril (15 mg.kg(-1).day(-1)) plus losartan (15 mg x kg(-1) x day(-1)) was administered to l-NAME/SHR (5.0 +/- 0.10 mg x kg(-1) x day(-1)) for 3 wk. Mean arterial pressure, total peripheral resistance, renal plasma flow, glomerular filtration rate, glomerular hydrostatic pressure, afferent and efferent glomerular arteriolar resistances, single nephron plasma flow, single nephron glomerular filtration rate, serum creatinine concentration, 24-h urinary protein excretion, and glomerular and arteriolar injury scores were determined. HCTZ reduced mean arterial pressure, total peripheral resistance, glomerular hydrostatic pressure, and afferent and efferent glomerular arteriolar resistances (P < 0.05, at least) but slightly increased renal plasma flow and single nephron plasma flow associated with reduced serum creatinine concentration, urinary protein excretion, and arteriolar injury score compared with l-NAME/SHR control. However, the combination of enalapril and/or losartan with HCTZ markedly improved each of these functions. These results demonstrated minor benefits of HCTZ monotherapy and a marked superiority of its combination with enalapril and/or losartan over HCTZ monotherapy on renoprotection in l-NAME/SHR, thereby providing strong evidence of their clinical benefits for hypertensive patients with renal functional impairment.