RESUMO
BACKGROUND: Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27. METHODS: Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-beta1, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA). RESULTS: SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 +/- 7.3 vs. 84.4 +/- 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-beta did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 +/- 6.6 vs. 50.2 +/- 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 +/- 0.40 vs. 4.07 +/- 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV. CONCLUSION: SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/patologia , Sinvastatina/farmacologia , Albuminúria/imunologia , Albuminúria/patologia , Animais , Divisão Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Matriz Extracelular/fisiologia , Hipertensão Renal/imunologia , Linfócitos/metabolismo , Linfócitos/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , RNA Mensageiro/análise , Ratos , Ratos Wistar , Cloreto de Sódio/farmacologia , Fator de Crescimento Transformador beta/genéticaRESUMO
Lymphocytes and macrophages infiltrate the kidney of spontaneously hypertensive rats (SHR) and interventions leading to their reduction are associated with improvement of the hypertension. The present studies examined the evolution of the interstitial inflammation in the natural course of the SHR to gain insight on the potential role of interstitial immune cell accumulation in the development of hypertension. We studied SHR and control WKY rats at 3 weeks (SHR-3 wk group, n = 11 and WKY-3 wk group, n = 10), 11 weeks (SHR-11 wk group, n = 5 and WKY-11 wk group, n = 5) and 24 weeks (SHR-24 wk group, n = 10 and WKY-24 wk group, n = 10). The SHR-3 wk group was normotensive and older SHR developed hypertension that was severe in the SHR-24 wk group. Tubulointerstitial accumulation of lymphocytes, macrophages, angiotensin II-positive cells, cells expressing the p65 DNA-binding subunit of NF-kappaB and activation of NF-kappaB in the kidney were all significantly increased (p < 0.01) in the prehypertensive SHR-3 wk group and augmented progressively, with the highest values in the SHR-24 wk group. The SHR-24 wk group showed increased (p < 0.001) helper (CD4) T cell infiltration and a high CD4/CD8 ratio. These findings are consistent with the possibility that activation of NF-kappaB and renal interstitial infiltration of immune cells may be part of the pathophysiologic process that drives hypertension in the SHR.
Assuntos
Hipertensão Renal/imunologia , Hipertensão Renal/patologia , Linfócitos/patologia , Macrófagos/patologia , NF-kappa B/metabolismo , Angiotensina II/metabolismo , Animais , Biópsia , Pressão Sanguínea , Relação CD4-CD8 , Creatinina/sangue , Hipertensão Renal/metabolismo , Linfócitos/imunologia , Macrófagos/imunologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Recent evidence indicates that interstitial infiltration of T cells and macrophages plays a role in the pathogenesis of salt-sensitive hypertension. The present review examines this evidence and summarizes the investigations linking the renal accumulation of immune cells and oxidative stress in the development of hypertension. The mechanisms involved in the hypertensive effects of oxidant stress and tubulointerstitial inflammation, in particular intrarenal ANG II activity, are discussed, focusing on their potential for sodium retention. The possibility of autoimmune reactivity in hypertension is raised in the light of the proinflammatory and immunogenic pathways stimulated by the interrelationship between oxidant stress and inflammatory response. Finally, we present some clinical considerations derived from the recognition of this interrelationship.
Assuntos
Hipertensão Renal/imunologia , Hipertensão Renal/metabolismo , Rim/metabolismo , Estresse Oxidativo/fisiologia , Linfócitos T/imunologia , Humanos , Rim/citologia , Rim/imunologia , Cloreto de Sódio na Dieta/farmacologiaRESUMO
Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 +/- 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg. kg(-1). day(-1)) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 +/- 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.
Assuntos
Hipertensão Renal/imunologia , Linfócitos/imunologia , Ácido Micofenólico/análogos & derivados , Nefrite Intersticial/imunologia , Proteinúria/imunologia , Animais , Peso Corporal , Proteínas Alimentares/farmacologia , Feminino , Hipertensão Renal/patologia , Hipertensão Renal/fisiopatologia , Imunossupressores/farmacologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Linfócitos/metabolismo , Linfócitos/patologia , Ácido Micofenólico/farmacologia , Nefrite Intersticial/patologia , Nefrite Intersticial/fisiopatologia , Estresse Oxidativo/imunologia , Proteinúria/patologia , Proteinúria/fisiopatologia , Ratos , Ratos Endogâmicos Lew , Cloreto de Sódio na Dieta/farmacologiaRESUMO
Immunocompetent cells infiltrate the kidney in several models of experimental hypertension. We have previously shown that reduction of this infiltrate results in prevention of salt-sensitive hypertension induced by short-term angiotensin II infusion and nitric oxide inhibition (Quiroz Y, Pons H, Gordon KI, Rincón J, Chávez M, Parra G, Herrera-Acosta J, Gómez-Garre D, Largo R, Egido J, Johnson RJ, and Rodríguez-Iturbe B. Am J Physiol Renal Physiol 281: F38-F47, 2001; Rodríguez-Iturbe B, Pons H, Quiroz Y, Gordon K, Rincón J, Chávez M, Parra G, Herrera-Acosta J, Gómez-Garre D, Largo R, Egido J, and Johnson RJ. Kidney Int 59: 2222-2232, 2001). We therefore studied whether hypertension could be controlled in genetically hypertensive rats [spontaneously hypertensive rats (SHR)] by the administration of 20 mg x kg(-1) x day(-1) of the immunosuppressive drug mycophenolate mofetil (MMF group; n = 35). Other SHR received vehicle (n = 35), and Wistar-Kyoto rats (n = 20) were used as controls. MMF or vehicle was given in two separate 4-wk periods, separated by a 3-wk interval. Systemic hypertension was reduced to normal levels in both periods of MMF treatment in association with a reduction in lymphocyte, macrophage, and angiotensin II-positive cells infiltrating the kidney. Oxidative stress was also reduced by MMF, as indicated by a reduction in urinary malondialdehyde (MDA), renal MDA content, and superoxide-positive cells, and was highly correlated with blood pressure levels. We conclude that the renal immune infiltrate plays a major role in the hypertension in SHR.