Activation of a local renin angiotensin system in podocytes by glucose

Durvasula, Raghu; Shankland, Stuart J.

doi:10.1152/ajprenal.00266.2007

Cited by 149 publications

(145 citation statements)

References 50 publications

(50 reference statements)

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“…41 Aliskiren was tested for its effects on cultured mouse podocytes exposed to high glucose levels. 25 In such podocytes, high glucose induced increased expression of renin mRNA and protein, and Ang II formation was detected. The latter was not inhibited by the ACEI captopril, but it was suppressed by aliskiren and the non-selective chymase inhibitor chymostatin.…”

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 98%

“…[25][26][27][28] Mesangial expression of Aogen and ACE has also been documented in renal tissue sections. 19,23 Mesangial cells synthesize Ang II 22,24 and aldosterone, the latter apparently through an Ang II-dependent mechanism.…”

Section: Intrarenal Raasmentioning

confidence: 98%

“…19,23 Mesangial cells synthesize Ang II 22,24 and aldosterone, the latter apparently through an Ang II-dependent mechanism. 29 Podocytes also produce Ang II 25,26,28 and aldosterone. 30 Angiotensin type 1 receptors are expressed on mesangial cells 19,24,31 and podocytes 26,28,32 and mineralocorticoid receptors are also expressed by both cell types.…”

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%

“…83 Thus, in vivo exposure of podocytes to aliskiren is predicted. As podocytes express a functional RAAS, [25][26][27][28] renin inhibition in these cells by aliskiren may Effect of aliskiren and enalapril on blood pressure (a) and albumin excretion (b) in mRen-2 rats. mRen-2 rats were treated with aliskiren or enalapril by subcutaneous osmotic minipumps.…”

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

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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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Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 98%

Section: Intrarenal Raasmentioning

confidence: 98%

Section: Intrarenal Raasmentioning

confidence: 99%

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

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

Feldman

2010

Hypertens Res

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Ginsenoside Rg1 inhibits angiotensin II‐induced podocyte autophagy via AMPK/mTOR/PI3K pathway

Tan

Wang

et al. 2016

Cell Biology International

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Recent researches have reported the extensive pharmacological activities of Ginsenoside Rg1 including antioxidant, anti-inflammatory, and anticancer properties. Furthermore Rg1 was also shown to protect various kinds of cells from self-digestion by its anti-autophagy activity. In previous studies, angiotensin II (Ang II), a key mediator of renin-angiotensin system, has been demonstrated to contribute to the progression of renal injury including abnormal autophagy. However, whether Rg1 can relieve Ang II-induced autophagy in podocyte as well as the underlying molecular mechanism remains to be elucidated. Here, we employed Ang II-treated podocyte as a model to investigate the effect of Rg1 on autophagy and the involved signal pathways. In the present study, we found that Ang II strongly promoted autophagy in immortalized mouse podocyte cells by observing the formation of autophagosomes and detecting the expression of autophagic marker, for example, LC3-II. Notably, compared to the Ang II-treated cells, treatment with Rg1 significantly inhibited the formation of autophagosomes and expression of autophagy-related proteins in Ang II pre-treated podocyte. Meanwhile, Rg1 downregulated the activity of AMPK and GSK-3β and upregulated the activity of P70S6K in Ang II-treated podocyte. In conclusion, these findings demonstrate that Ang II promotes autophagy in podocyte, and Rg1 effectively attenuates this process through AMPK/mTOR/PI3K pathway, suggesting that Rg1 may be beneficial to alleviate podocyte injury.

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Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

228

178

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Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a “tubulocentric” concept of early diabetic kidney function. The latter also explains the “salt paradox” of the diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.

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Activation of a local renin angiotensin system in podocytes by glucose

Cited by 149 publications

References 50 publications

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

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

Ginsenoside Rg1 inhibits angiotensin II‐induced podocyte autophagy via AMPK/mTOR/PI3K pathway

Pathophysiology of the Diabetic Kidney

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