High glucose concentration stimulates intracellular renin activity and angiotensin II generation in rat mesangial cells

Vidotti, Daniela Berguio; Casarini, Dulce Elena; Cristovam, Priscila Cardoso; Leite, Cléber Aparecido; Schor, Nestor; Boim, Miriam Aparecida

doi:10.1152/ajprenal.00371.2003

Cited by 204 publications

(208 citation statements)

References 40 publications

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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%

“…[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. 29 Podocytes also produce Ang II 25,26,28 and aldosterone.…”

Section: Intrarenal Raasmentioning

confidence: 99%

“…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. 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.…”

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%

“…However, some of the label seen in glomeruli may have reflected aliskiren bound to renin that possibly was present in the mesangial matrix. In addition, as aliskiren can penetrate cultured cardiomyocytes, 98 the drug may have entered mesangial cells and podocytes, both of which express renin 20,[24][25][26] to which aliskiren could bind. Furthermore, the unequivocal evidence for labeled aliskiren in the walls of renal vessels prompts the proposal that this DRI can enter JG cells, and possibly incorporate into forming or formed renin granules.…”

Section: Aliskiren Localizes In the Kidneymentioning

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: Intrarenal Raasmentioning

confidence: 99%

Section: Intrarenal Raasmentioning

confidence: 99%

Section: Intrarenal Raasmentioning

confidence: 99%

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

Section: Aliskiren Localizes In the Kidneymentioning

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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Nanoparticles Mimicking Viral Cell Recognition Strategies Are Superior Transporters into Mesangial Cells

et al. 2020

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Poor drug availability in the tissue of interest is a frequent cause of therapy failure. While nanotechnology has developed a plethora of nanocarriers for drug transport, their ability to unequivocally identify cells of interest remains moderate. Viruses are the ideal nanosized carriers as they are able to address their embedded nucleic acids with high specificity to their host cells. Here, it is reported that particles endowed with a virus‐like ability to identify cells by three consecutive checks have a superior ability to recognize mesangial cells (MCs) in vivo compared to conventional nanoparticles. Mimicking the initial viral attachment followed by a stepwise target cell recognition process leads to a 5‐ to 15‐fold higher accumulation in the kidney mesangium and extensive cell uptake compared to particles lacking one or both of the viral traits. These results highlight the relevance that the viral cell identification process has on specificity and its application on the targeting strategies of nanomaterials. More so, these findings pave the way for transporting drugs into the mesangium, a tissue that is pivotal in the development of diabetic nephropathy and for which currently no efficient pharmacotherapy exists.

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High glucose increases extracellular matrix production in pancreatic stellate cells by activating the renin–angiotensin system

Hong

Kim

et al. 2006

J of Cellular Biochemistry

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Pancreatic stellate cells (PSCs) are involved in pancreatic inflammation and fibrosis. Recent studies have shown that blocking the renin-angiotensin system (RAS) attenuates pancreatic inflammation and fibrosis. However, there are few data about the direct effects of high glucose on extracellular matrix (ECM) protein synthesis and angiotensin II (Ang II) induction in PSCs. PSCs were isolated from male Sprague-Dawley rats and cultured in medium containing 5.5 mM (LG group) or 27 mM D-glucose (HG group). Levels of Ang II and transforming growth factor-beta (TGF-beta) in culture media were measured and Ang II-positive cells were counted. We used real-time polymerase chain reaction (PCR) to detect Ang II receptor expression and Western blot analysis for the expression of ECM proteins such as connective-tissue growth factor (CTGF) and collagen type IV. Cells were also treated with an Ang II-receptor antagonist (candesartan, 10 microM) or angiotensin-converting enzyme (ACE) inhibitor (ramiprilat, 100 nM). Thymidine uptake by PSCs increased fourfold with high glucose treatment. Ang II levels and the proportion of Ang II-positive PSCs were significantly increased after 6 h under high-glucose conditions. TGF-beta concentrations also increased significantly with high glucose. After 72 h, the expression of CTGF and collagen type IV proteins in high-glucose cultures increased significantly and this increase was effectively attenuated by the candesartan or the ramiprilat. All together, high glucose induced PSCs proliferation and ECM protein synthesis, and these effects were attenuated by an Ang II-receptor antagonist. The data suggest that pancreatic inflammation and fibrosis aggravated by hyperglycemia, and Ang II play an important role in this pathogenesis.

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High glucose concentration stimulates intracellular renin activity and angiotensin II generation in rat mesangial cells

Cited by 204 publications

References 40 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

Nanoparticles Mimicking Viral Cell Recognition Strategies Are Superior Transporters into Mesangial Cells

High glucose increases extracellular matrix production in pancreatic stellate cells by activating the renin–angiotensin system

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