Cilnidipine suppresses podocyte injury and proteinuria in metabolic syndrome rats: possible involvement of N-type calcium channel in podocyte

Fan, Yu-Yan; Kohno, Masakazu; Nakano, Daisuke; Ohsaki, Hiroyuki; Kobori, Hiroyuki; Diah, Suwarni; Ohashi, Naro; Hitomi, Hirofumi; Asanuma, Katsuhiko; Noma, Takahisa; Tomino, Yasuhiko; Fujita, Toshiro; Nishiyama, Akira

doi:10.1097/hjh.0b013e328336ade3

Cited by 41 publications

(54 citation statements)

References 44 publications

(50 reference statements)

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“…Also, albumin overload was shown to increase intracellular calcium ion concentration ([Ca 2ϩ ] i ) in podocytes both via the Ca 2ϩ influx and the release of the intracellular Ca 2ϩ stores (8). A number of cation channels have been identified to cause Ca 2ϩ influx in podocytes (16,35,58,68). Among them, TRPC6 has been attracting most attention.…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

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Glomerulosclerosis is featured by accumulation of the extracellular matrixes in the glomerulus. We showed previously that activation of the small GTPase RhoA in podocytes induces heavy proteinuria and glomerulosclerosis in the mouse. In the current study, we investigated the mechanism by which RhoA stimulates the production of one of the extracellular matrixes, fibronectin, by podocytes, specifically testing the role of nuclear factor of activated T cells (NFAT). Expression of constitutively active RhoA in cultured podocytes activated the fibronectin promoter, upregulated fibronectin protein, and activated NFAT. Expression of constitutively active NFAT in podocytes also activated the fibronectin promoter and upregulated fibronectin protein. RhoA-induced NFAT activation and fibronectin upregulation were both dependent on the calcium/calmodulin pathway and Rho kinase. NFAT activation was also observed in vivo in the rat and mouse models of podocyte injury and proteinuria, and NFAT inhibition ameliorated fibronectin upregulation in the latter. RhoA activation induced a rise of intracellular calcium ion concentration ([Ca2+]i), which was at least in part dependent on the transient receptor potential canonical 6 (TRPC6) cation channel. The results indicate that RhoA activates NFAT by inducing a rise of [Ca2+]i in podocytes, which in turn contributes to fibronectin upregulation. This pathway may be responsible for the pathogenesis of certain glomerular diseases such as hypertension-mediated glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

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“…Moreover, even previous studies reported better renoprotective effects of cilnidipine than amlodipine. 26,27 Cilnidipine was shown to prevent the increase in renal angiotensin II content in spontaneously hypertensive rat/ND mcr-cp (an obese spontaneously hypertensive model). 26 In addition, it reduced renal ACE activity and renal aldosterone content in uninephrectomized deoxycorticosterone-salt hypertensive rats.…”

Section: Discussionmentioning

confidence: 99%

“…26,27 Cilnidipine was shown to prevent the increase in renal angiotensin II content in spontaneously hypertensive rat/ND mcr-cp (an obese spontaneously hypertensive model). 26 In addition, it reduced renal ACE activity and renal aldosterone content in uninephrectomized deoxycorticosterone-salt hypertensive rats. 27 However, in the present study, the activity of renal RAS system in hypertensive patients was not evaluated.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective and antioxidant effects of cilnidipine in hypertensive patients

Soeki

Kitani²,

Kusunose

et al. 2012

Hypertens Res

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Cilnidipine, an L/N-type calcium channel blocker (CCB), has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than amlodipine, an L-type CCB. The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles. However, the precise mechanism of the renoprotective effect of cilnidipine remains unknown. Because cilnidipine exerted significantly higher antioxidant activity than amlodipine in cultured human mesangial cells, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing oxidative stress. A total of 35 hypertensive patients receiving a renin-angiotensin system inhibitor were randomly assigned to a cilnidipine (n ¼ 18; 10 mg per day cilnidipine titrated to 20 mg per day) or amlodipine (n ¼ 17; 5 mg per day amlodipine titrated to 10 mg per day) group; the target blood pressure (BP) was set at 130/85 mmHg. After 6 months of treatment, systolic and diastolic BPs were significantly reduced in both of the groups, without any significant difference between the groups. The urinary albumin, 8-hydroxy-2 0 -deoxyguanosine (OHdG) and liver-type fatty-acid-binding protein (L-FABP) to creatinine ratios significantly decreased in the cilnidipine group (Po0.05) compared with those in the amlodipine group. The reductions in urinary albumin, 8-OHdG and L-FABP were not correlated with the change in systolic BP. In conclusion, cilnidipine, but not amlodipine, ameliorated urinary albumin excretion and decreased urinary 8-OHdG and L-FABP in the hypertensive patients. Cilnidipine probably exerts a greater renoprotective effect through its antioxidative properties.

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“…For cilnidipine the result could be explained by the less activation of RAS. A recent report suggests that cilnidipine suppressed the development of proteinuria greater than amlodipine possibly through inhibiting N-type calcium channel-dependent podocyte injury in SHR/ND [36]. For efonidipine, the result might be explained by suppression effect on transcription of aldosterone synthase (CYP11B2) [37].…”

Section: Discussionmentioning

confidence: 99%

A crossover comparison of urinary albumin excretion as a new surrogate marker for cardiovascular disease among 4 types of calcium channel blockers

Konoshita

Makino

Kimura

et al. 2013

International Journal of Cardiology

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40.6 (18.7-94.7). By all agents, significant augmentations were observed in PRA, angiotensin I and angiotensin II (AngII). AngII at cilnidipine was significantly lower than that at amlodipine. PAC at cilnidipine and efonidipine was significantly lower than that at amlodipine. Nifedipine CR significantly reduced ANP concentration. Conclusions: It is revealed that only nifedipine CR and cilnidipine could reduce albuminuria statistically. Thus, it is suggested that the 2 CCBs might be favorable for organ protection in hypertensives.

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Cilnidipine suppresses podocyte injury and proteinuria in metabolic syndrome rats: possible involvement of N-type calcium channel in podocyte

Cited by 41 publications

References 44 publications

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Renoprotective and antioxidant effects of cilnidipine in hypertensive patients

A crossover comparison of urinary albumin excretion as a new surrogate marker for cardiovascular disease among 4 types of calcium channel blockers

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