N-type Calcium Channel Inhibition With Cilnidipine Elicits Glomerular Podocyte Protection Independent of Sympathetic Nerve Inhibition

Lei, Bai; Nakano, Daisuke; Fujisawa, Yoshihide; Liu, Ya; Hitomi, Hirofumi; Kobori, Hiroyuki; Mori, Hideki; Masaki, Tsutomu; Asanuma, Katsuhiko; Tomino, Yasuhiko; Nishiyama, Akira

doi:10.1254/jphs.12075fp

Cited by 13 publications

(9 citation statements)

References 46 publications

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“…Several studies have suggested that the increase in renal Ang II level contributes to the development of renal disease (23, 39 – 41). However, there was no difference in proteinuria at week 4 of Ang I infusion between temocapril- and olmesartan-treated groups.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin-Converting Enzyme Inhibitor Does Not Suppress Renal Angiotensin II Levels in Angiotensin I^|^ndash;Infused Rats

et al. 2013

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Angiotensin II (Ang II) infusion into rats elevates local angiotensin II levels through an AT1 receptor–dependent pathway in the kidney. We examined whether treatment with an angio-tensin-converting enzyme (ACE) inhibitor, temocapril, or an AT1-receptor blocker, olmesartan, prevented elevation of Ang II levels in the kidney of angiotensin I (Ang I)-infused rats. Rats were infused with Ang I (100 ng/min) and treated with temocapril (30 mg/kg per day, n = 10) or olmesartan (10 mg/kg per day, n = 9) for 4 weeks. Ang I infusion significantly elevated blood pressure compared with vehicle-infused rats (n = 6). Treatment with temocapril or olmesartan suppressed Ang I–induced hypertension. Temocapril suppressed both plasma and renal ACE activity. Ang I infusion increased Ang II content in the kidney. Interestingly, temocapril failed to reduce the level of Ang II in the kidney, while olmesartan markedly suppressed an increase in renal Ang II levels. These results suggest a limitation of temocapril and a benefit of olmesartan to inhibit the renal renin–angiotensin system and suggest the possible existence of an ACE inhibitor–insensitive pathway that increases Ang II levels in rat kidney.

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Section: Discussionmentioning

confidence: 99%

“…The oligonucleotide primer sequences of GAPDH and AGT and PCR conditions were as described previously (23, 24). The primer sequences of ACE2 were as follows: ACE2 forward, 5′-CCCAGAGAACAGTGGACCAAAA-3′ and reverse, 5′-GCTCCACCACACCAACGAT-3′.…”

Section: Methodsmentioning

confidence: 99%

Angiotensin-Converting Enzyme Inhibitor Does Not Suppress Renal Angiotensin II Levels in Angiotensin I^|^ndash;Infused Rats

et al. 2013

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“…L/Ntype CCBs has been shown to provide renal protection by decreasing the activity of the sympathetic nervous system and the RAAS, resulting in vasodilation of both arterioles, inhibition of podocyte injury and decrease in proteinuria. [44][45][46][47][48] With respect to L/T-type CCBs, T-type channels have an important role in the kidney, mediating efferent arteriole tone, and combined T-and L-type CCBs might have a therapeutic advantage over selective L-type CCBs by providing renoprotection via a lower glomerular pressure and filtration fraction. 49 Hypertension and proteinuria are well-recognized risk factors for predicting progression of CKD 10 and cardiovascular morbidity and mortality.…”

Section: Renal Effects Of N-and T-type Ccbmentioning

confidence: 99%

Effect of N- and T-type calcium channel blocker on proteinuria, blood pressure and kidney function in hypertensive patients: a meta-analysis

et al. 2015

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The combination of a calcium channel blocker (CCB) and a blocker of the renin-angiotensin-aldosterone system (RAAS) is recommended in clinical practice guidelines. L/N- and L/T-type CCBs might provide an additional effect on lowering proteinuria. Therefore, we conducted a meta-analysis to assess the efficacy of L/N- and L/T-type CCBs in hypertensive patients with proteinuria. We searched MEDLINE, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for single-arm studies and randomized controlled trials (RCTs) that examined the effect of L/N- and L/T-type CCBs as add-on therapy compared with standard antihypertensive regimen for proteinuria on hemodynamic and kidney-related parameters in hypertensive patients with proteinuria. Random-effect model meta-analyses were used to compute changes in the outcomes of interest. We identified 17 RCTs, representing 1905 patients. By meta-analysis, L/N- and L/T-type CCB add-on therapy did not yield significant changes in systolic and diastolic blood pressure compared with standard treatment, but there was a significant lowering of the pulse rate. However, L/N- and L/T-type CCBs resulted in a significant standardized net decrease in albuminuria and proteinuria (-1.01; 95% confidence interval (CI), -1.78 to -0.23; P=0.01), and a standardized net improvement in the estimated glomerular filtration rate and serum creatinine (0.23; 95% CI, 0.11 to 0.35, P<0.001; and -0.25; 95% CI, -0.46 to -0.03; P=0.02, respectively). Despite no additional lowering effect on blood pressure, L/N- and L/T-type CCBs combined with a blocker of the RAAS provided a decrease in proteinuria and improvement in kidney function. Further studies are required to establish the long-term kidney benefits of this combination therapy.

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“…However, in addition to these actions, we showed possible functional roles of the N-type calcium channel in podocytes. Previous reports showed that glomerular podocytes express the N-type calcium channel 13 27 . Fan et al .…”

Section: Discussionmentioning

confidence: 98%

“…Because N-type calcium channels exist at synaptic nerve endings 26 in both the afferent and efferent arterioles, and the blockade of the N-type calcium channel inhibits norepinephrine release 26 , such sympatholytic effect of the N-type calcium channel ablation may have worked to ameliorate glomerular injury in our study. Cilnidipine showed similar antihypertensive effects and suppression of proteinuria both in innervated and denervated spontaneous hypertensive rat (SHR) 27 , thus suggesting that renal sympathetic nerves may have a limited contribution to its renoprotective effects. In our study, albuminuria as well as glomerular histological changes were significantly alleviated in db/db Ca v 2.2 +/− mice and cilnidipine-treated diabetic mice without reduction of urinary catecholamine levels, further providing a possibility for mechanisms independent of the sympathetic nerve activity.…”

Section: Discussionmentioning

confidence: 99%

Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure

Ohno

Yokoi

Mori

et al. 2016

Sci Rep

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Pharmacological blockade of the N- and L-type calcium channel lessens renal injury in kidney disease patients. The significance of specific blockade of α1 subunit of N-type calcium channel, Cav2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Cav2.2−/− mice with db/db (diabetic) mice on the C57BLKS background. Cav2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Cav2.2−/− mice significantly reduced urinary albumin excretion, glomerular hyperfiltration, blood glucose levels, histological deterioration and systolic blood pressure (SBP) with decreased urinary catecholamine compared to diabetic Cav2.2+/+ mice. Interestingly, diabetic heterozygous Cav2.2+/− mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Cav2.2+/+ mice. Consistently, diabetic mice with cilnidipine, an N-/L-type calcium channel blocker, showed a reduction in albuminuria and improvement of glomerular changes compared to diabetic mice with nitrendipine. In cultured podocytes, depolarization-dependent calcium responses were decreased by ω-conotoxin, a Cav2.2-specific inhibitor. Furthermore, reduction of nephrin by transforming growth factor-β (TGF-β) in podocytes was abolished with ω-conotoxin, cilnidipine or mitogen-activated protein kinase kinase inhibitor. In conclusion, Cav2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes.

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N-type Calcium Channel Inhibition With Cilnidipine Elicits Glomerular Podocyte Protection Independent of Sympathetic Nerve Inhibition

Cited by 13 publications

References 46 publications

Angiotensin-Converting Enzyme Inhibitor Does Not Suppress Renal Angiotensin II Levels in Angiotensin I^|^ndash;Infused Rats

Angiotensin-Converting Enzyme Inhibitor Does Not Suppress Renal Angiotensin II Levels in Angiotensin I^|^ndash;Infused Rats

Effect of N- and T-type calcium channel blocker on proteinuria, blood pressure and kidney function in hypertensive patients: a meta-analysis

Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure

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