Mechanism of Increased Angiotensin II Levels in Glomerular Mesangial Cells Cultured in High Glucose

Singh, Rekha; Singh, Ashok K.; Alavi, Nahid; Leehey, David J.

doi:10.1097/01.asn.0000060804.40201.6e

Cited by 138 publications

(132 citation statements)

References 26 publications

(63 reference statements)

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“…37 Intra-renal renin and angiotensinogen levels are induced in diabetic animals, 38,39 and high glucose has been shown to stimulate renin and Ang II synthesis in mesangial cells and podocytes. 37,40,41 Further, the role of notch I signaling have also been recently associated with pathogenic VEGF induction and podocytopathy. 42 It remains to be determined if the use of A 2B AR antagonist could also intercept the activation of the renin-angiotensin system or notch I signaling.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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Diabetic nephropathy ranks as the most devastating kidney disease worldwide. It characterizes in the early onset by glomerular hypertrophy, hyperfiltration and mesangial expansion. Experimental models show that overproduction of vascular endothelial growth factor (VEGF) is a pathogenic condition for podocytopathy; however the mechanisms that regulate this growth factor induction are not clearly identified. We determined that the adenosine A 2B receptor (A 2B AR) mediates VEGF overproduction in ex vivo glomeruli exposed to high glucose concentration, requiring PKCa and Erk1/2 activation. The glomerular content of A 2B AR was concomitantly increased with VEGF at early stages of renal disease in streptozotocin-induced diabetic rats. Further, in vivo administration of an antagonist of A 2B AR in diabetic rats blocked the glomerular overexpression of VEGF, mesangial cells activation and proteinuria. In addition, we also determined that the accumulation of extracellular adenosine occurs in glomeruli of diabetic rats. Correspondingly, raised urinary adenosine levels were found in diabetic rats. In conclusion, we evidenced that adenosine signaling at the onset of diabetic kidney disease is a pathogenic event that promotes VEGF induction.

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Section: Discussionmentioning

confidence: 99%

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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“…The rats were fed with standard diet. Primary culture of GMCs was performed according to the literature with slight modifications (Singh et al 2003). The rats were anesthetized, and the bilateral kidneys were isolated.…”

Section: Methodsmentioning

confidence: 99%

Attenuated mesangial cell proliferation related to store-operated Ca2+ entry in aged rat: the role of STIM 1 and Orai 1

Shen

Zhu

Zhang

et al. 2013

AGE

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Store-operated Ca 2+ entry (SOCE) is a common and ubiquitous mechanism regulating Ca 2+ influx into cells and participates in numerous biological processes including cell proliferation. Glomerular mesangial cells (GMCs) play a role in the regulation of the glomerular filtration rate. From a clinical point of view, many physiological functions alter with age. In the present study, we used angiotensin II, glucagon, and the sarco/endoplasmic reticulum membrane Ca 2+ pump inhibitor thapsigargin to deplete the internal Ca 2+ stores for the activation of SOCE. We found that SOCE was significantly attenuated in GMCs from aged (22-month-old) rats. The expression of SOCErelated components, stromal interaction molecule 1 (STIM 1) and Orai 1, in freshly isolated glomeruli notably decreased, and STIM 1 and Orai 1 puncta formation significantly reduced in primary-cultured GMCs in aged rats. Moreover, specific knockdown of STIM 1 and Orai 1 by small interfering RNA markedly suppressed SOCE and cell proliferation of GMCs isolated from young (3-month-old) rats. We conclude that the attenuation of GMCs proliferation can be attributed to the decreased SOCE partially caused by reduced expression of STIM 1 and Orai 1.

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“…Gene and protein expression of angiotensinogen (Aogen), renin and ACE has been reported in cultured glomerular mesangial cells [12][13][14][15][16][17][18][19][20][21][22][23][24] and podocytes. [25][26][27][28] Mesangial expression of Aogen and ACE has also been documented in renal tissue sections.…”

Section: Intrarenal Raasmentioning

confidence: 99%

“…The intrarenal RAAS is thought to be activated during diabetes, based on in vitro and in vivo evidence. 21,22,24,25,48,54,55,69,78 Therefore, the effect of renin inhibition in diabetic conditions is of great interest.…”

Section: Testing Aliskiren In Animal Modelsmentioning

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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Mechanism of Increased Angiotensin II Levels in Glomerular Mesangial Cells Cultured in High Glucose

Cited by 138 publications

References 26 publications

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Attenuated mesangial cell proliferation related to store-operated Ca2+ entry in aged rat: the role of STIM 1 and Orai 1

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

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