Activation of a local tissue angiotensin system in podocytes by mechanical strain11See Editorial by Kriz, p. 333.

Durvasula, Raghu; Petermann, Arndt T.; Hiromura, Keiju; Blonski, Mary; Pippin, Jeffrey W.; Mündel, Peter; Pichler, Raimund; Griffin, Siân; Couser, William G.; Shankland, Stuart J.

doi:10.1111/j.1523-1755.2004.00362.x

Cited by 287 publications

(264 citation statements)

References 38 publications

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“…16 Cultured podocytes exposed to mechanical stress enhance angiotensin II type 1 receptor gene expression, which results in podocyte injury. 17 In the present study, the desmin staining score, which shows the degree of damaged podocytes, was significantly reduced by irbesartan. These previous observations, along with the findings of our study, show that blockade of angiotensin II is useful for attenuation of glomerulosclerosis and proteinuria in DS rats after high salt loading.…”

Section: Discussionsupporting

confidence: 55%

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

2010

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Angiotensin receptor blockers (ARBs) or T-and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg À1 ), efonidipine (30 mg kg À1 ), irbesartan (60 mg kg À1 )+efonidipine (30 mg kg À1 ), amlodipine (3 mg kg À1 ), or irbesartan (60 mg kg À1 )+amlodipine (3 mg kg À1 ) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine-and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22 phox , transforming growth factor-b, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T-and L-type CCB might produce a powerful renal protective effect. INTRODUCTIONKidneys have an important role not only in the homeostasis of water and electrolyte balance but also in the regulation of blood pressure. Angiotensin II is a crucial peptide for regulating blood pressure by slow and rapid pressor responses. The main functions of slow response are augmentation of sodium reabsorption in the proximal tubules and release of aldosterone from the adrenal cortex, whereas the main functions of rapid response are direct contractile response in peripheral resistance arteries and enhancement of peripheral noradrenergic neurotransmission. Therefore, blockade of angiotensin II is a useful antihypertensive strategy. In addition, angiotensin II directly increases mesangial matrix formation by stimulating transforming growth factor (TGF)-b expression. 1 Inhibition of angiotensin II function induces dilation of efferent arterioles, and this mechanism contributes to amelioration of glomerular hypertension, resulting in a decrease in mesangial matrix formation. 2 Therefore, blockade of angiotensin II is also useful for preventing glomerular injury.Calcium channel blockers (CCBs), such as angi...

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Section: Discussionsupporting

confidence: 55%

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

2010

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“…These findings indicate that under pathologic conditions, an upregulation of chymase occurs and increased local AngII generation cannot be attenuated by ACE inhibitors. Mechanical stress of podocytes stimulates local AngII synthesis by non-ACE pathways that presumably involve chymase (6), yet the exact role of chymase-mediated AngII formation for renal disease in humans is unclear, and ACE inhibitors clearly slow progression of disease.…”

Section: Generation Of Angii and Other Peptidesmentioning

confidence: 99%

Renin-Angiotensin-Aldosterone System and Progression of Renal Disease

Rüster

Wolf

2006

Journal of the American Society of Nephrology

398

306

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Inhibition of the renin-angiotensin-aldosterone system (RAAS) is one of the most powerful maneuvers to slow progression of renal disease. Angiotensin II (AngII) has emerged in the past decade as a multifunctional cytokine that exhibits many nonhemodynamic properties, such as acting as a growth factor and profibrogenic cytokine, and even having proinflammatory properties. Many of these deleterious functions are mediated by other factors, such as TGF-␤ and chemoattractants that are induced in the kidney by AngII. Moreover, understanding of the RAAS has become much more complex in recent years with the identification of novel peptides (e.g., AngIV) that could bind to specific receptors, elucidating deleterious effects, and non-angiotensin-converting enzyme (ACE)-mediated generation of AngII. The ability of renal cells to produce AngII in a concentration that is much higher than what is found in the systemic circulation and the observation that aldosterone may be engaged directly in profibrogenic processes independent of hypertension have added to the complexity of the RAAS. Even renin has now been identified to have a "life on its own" and mediates profibrotic effects via binding to specific receptors. Finally, drugs that are used to block the RAAS, such as ACE inhibitors or certain AngII type 1 receptor antagonists, may have properties on cells independent of AngII (ACE inhibitor-mediated outside-inside signaling and peroxisome proliferatoractivated receptor-␥ stimulatory effects of certain sartanes). Although blockade of the RAAS with ACE inhibitors, AngII type 1 receptor antagonists, or the combination of both should be part of every strategy to slow progression of renal disease, a better understanding of the novel aspects of the RAAS should contribute to the development of innovative strategies not only to completely halt progression but also to induce regression of human renal disease.

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“…58 Studies in cultured podocytes have demonstrated that these cells possess an independent renin-Ang system (RAS) that is activated by high glucose levels 59 and mechanical stretch. 60 In turn, activation of the podocyte RAS leads to an increase in podocyte apoptosis 60 and also to a reduction in the expression of nephrin. 61 Nephrin is a key component of the slit diaphragm, 52,61 a junction connecting the foot process of neighboring podocytes, which represents the major restriction site of protein filtration.…”

Section: In Vitro Studies Searching For the Mechanism Of The Interactmentioning

confidence: 99%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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Activation of a local tissue angiotensin system in podocytes by mechanical strain11See Editorial by Kriz, p. 333.

Abstract: Mechanical strain leads to up-regulation of the AT1R and increased angiotensin II production in conditionally immortalized podocytes. The resulting activation of a local tissue angiotensin system leads to an increase in podocyte apoptosis, mainly in an AT1R-mediated fashion.

Cited by 287 publications

References 38 publications

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

Renin-Angiotensin-Aldosterone System and Progression of Renal Disease

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

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