Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.

Kubo, Shoji; Border, Wayne A.; Miller, Dale; Noble, Nancy A.

doi:10.1172/jci117251

Cited by 1,007 publications

(704 citation statements)

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“…19 In addition, a complex and rich interaction between TGF-b and the renin-angiotensin system has been observed in the kidneys of experimental animals with chronic kidney diseases. 20 Previous studies demonstrated that Ang II stimulates the synthesis of TGF-b in cultured rat vascular smooth muscle cells, 21 rat glomerular mesangial cells 22 and cultured murine proximal tubular cells. 23 In addition, blocking Ang II with ACE inhibitors or Long-term effects of HRP on 2K1C kidneys M Ryuzaki et al Ang II type 1 receptor antagonists decreased the overexpression of TGF-b in animals with chronic kidney diseases, 20 and the blocking of prorenin binding to the (P)RR by HRP inhibited the elevated Ang II levels in the kidneys of the animals with diabetes 4 and hypertension.…”

Section: Long-term Effects Of Hrp On 2k1c Kidneys M Ryuzaki Et Almentioning

confidence: 99%

Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

et al. 2010

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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)-b 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-b 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.

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Section: Long-term Effects Of Hrp On 2k1c Kidneys M Ryuzaki Et Almentioning

confidence: 99%

Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

et al. 2010

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“…29,33,34 The likely importance of the local glomerular RAAS relates to the pathogenesis of glomeruloscleorsis and the loss of glomerular permselectivity observed in many glomerular diseases. In cultured mesangial cells, Ang II [35][36][37] and aldosterone 38,39 provoke synthesis of extracellular matrix (ECM) proteins that accumulate in glomerulosclerosis. In podocytes, Ang II has been shown to induce apoptosis, 40,41 cytoskeletal rearrangement 42 and nephrin loss 43 in podocytes, alterations that have been linked to albuminuria.…”

Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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“…Numerous studies including data from our own laboratory indiStudies have provided evidence that angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists attenuate diabetic glomerulosclerosis and slow the progression of diabetic kidney disease [1, 2, cate that hyperglycemia induces an increase in TGF-β1 protein and mRNA expression in experimental and human diabetes [15,19,20,21] and in cultured mesangial cells [22,23,24]. Although previous investigations clearly demonstrated that ang II stimulates the synthesis of extracellular matrix proteins through an enhanced TGF-β1 expression in mesangial cells [25] the molecular mechanism of ang II-induced TGF-β1 gene activation, particularly the detailed localization of the ang II responsive elements on the TGF-β1 promoter, have not been studied yet.…”

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confidence: 99%

Angiotensin II induces human TGF-β1 promoter activation: similarity to hyperglycaemia

et al. 2002

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Aims/hypothesis. Activation of the renal renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy. Because previous in vitro studies demonstrated the angiotensin II (ang II)-mediated up-regulation of the prosclerotic transforming growth factor β1 (TGF) we studied the molecular mechanism of ang II-induced TGF-β1 gene activation. Methods. Mesangial cells were stimulated with 100 nmol/l ang II with or without inhibitors of protein kinase C (PKC) and p38 MAPK and the TGF-β1 promoter activity was determined by promoter-reporter assays. The effect of ang II on the binding of nuclear proteins to the regulatory AP-1 site B, previously shown to mediate the high glucose-response of the TGF-β1 promoter, was studied by electrophoretic mobility shift assays. Results. Ang II enhanced the activity of the TGF-β1 promoter fragment -453/+11 approximately 1.6-fold.Mutation of each of two AP-1 binding sites or inhibition of the PKC-and p38 MAPK-dependent pathways blocked the ang II-stimulated activity completely. Furthermore, ang II activated the binding of nuclear proteins to the AP-1 box B of the TGF-β1 promoter. These effects were similar to those previously observed with high glucose. Co-incubation with ang II and high glucose had no additive effect on TGF-β1 promoter activity, protein binding to the AP-1 box B or activation of p38 MAPK. Conclusion/interpretation. The findings indicate that ang II and hyperglycaemia stimulate the TGF-β1 gene activation through the same PKC-and p38 MAPK-dependent pathways by the same regulatory elements of the TGF-β1 promoter. Our data could also be relevant for e.g. hypertension-induced glomerulosclerosis. [Diabetologia (2002) 45:890-898]

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Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.

Cited by 1,007 publications

References 46 publications

Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Angiotensin II induces human TGF-β1 promoter activation: similarity to hyperglycaemia

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