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N-Type Calcium Channel Inhibition with Cilnidipine Elicits Glomerular Podocyte Protection Independent of Sympathetic Nerve Inhibition

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N-Type Calcium Channel Inhibition with Cilnidipine Elicits Glomerular Podocyte Protection Independent of Sympathetic Nerve Inhibition J Pharmacol Sci 119, 359 – 367 (2012) Journal of Pharmacological Sciences © The Japanese Pharmacological Society Full Paper N-type Calcium Channel Inhibition With Cilnidipine Elicits Glomerular Podocyte Protection Independent of Sympathetic Nerve Inhibition Bai Lei1, Daisuke Nakano1,*, Yoshihide Fujisawa1, Ya Liu1, Hirofumi Hitomi1, Hiroyuki Kobori1, Hirohito Mori2, Tsutomu Masaki2, Katsuhiko Asanuma3, Yasuhiko Tomino3, and Akira Nishiyama1 1Department of Pharmacology, 2Department of Gastroenterology, Kagawa University Medical School, Kagawa 761-0793, Japan 3Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan Received March 25, 2012; Accepted June 17, 2012 Abstract. We recently demonstrated that cilnidipine, an L/N-type calcium channel blocker, elicits protective effects against glomerular podocyte injury, in particular, in obese hypertensive rats that express the N-type calcium channel (N-CC). Since the N-CC is known to be expressed in sympathetic nerve endings, we evaluated the reno-protective effects of cilnidipine in innervated and denervated spontaneously hypertensive rats (SHR). Male SHR were uninephrectomized and fed 4% high-salt diet (HS-UNX-SHR). Animals were divided into groups, as follows, and observed from 9 to 27 weeks of age: 1) vehicle (n = 14), 2) vehicle plus renal-denervation (n = 15), 3) cilnidipine (50 mg/kg per day, p.o.; n = 10), and 4) cilnidipine plus renal-denervation (n = 15). Renal denervation attenuated elevations in blood pressure, but failed to suppress urinary protein excretion and podocyte injury in HS-UNX-SHR. Cilnidipine in both innervated and denervated HS-UNX-SHR similarly induced significant antihypertensive effects, as well as suppressing the urinary protein excretion and podocyte injury, compared to vehicle-treated HS-UNX-SHR. These data indicate that renal nerves have a limited contribution to the cilnidipine-induced reno-protective effects in HS-UNX-SHR. Keywords: cilnidipine, hypertension, N-type calcium channel, podocyte, renal sympathetic nerve Introduction The reno-protective effects of cilnidipine may be in- duced via its inhibitory effects on N-type calcium chan- Calcium-channel blockers (CCBs) are widely used in nels (N-CCs). N-CCs are distributed throughout sympa- the treatment of hypertension and its associated compli- thetic nerve endings and are widely believed to be cations. Cilnidipine is an L/N-type CCB that has been involved in controlling the release of neurotransmitters recently shown to suppress the development of urinary from the nerve terminals of sympathetic neurons. This protein excretion in hypertensive patients (1 – 3). A N-CC–induced release of neurotransmitters has been previous study conducted by our group showed that implicated in the over-activation of sympathetic nerves cilnidipine prevents the development of proteinuria and (5, 6), which could also be involved in the pathogenesis glomerular podocyte injury in rats with metabolic syn- of resistant hypertension (7) and chronic renal diseases drome (4). These reno-protective effects cannot be simply (8, 9). We recently demonstrated the immunoreactivity explained by the hypotensive effects of cilnidipine, as its of N-CCs in vascular walls, possibly in the nerves in reno-protective effects were greater than those of amlo- adventitia, distal tubules, and renal podocytes and that dipine, an L-type CCB, with similar levels of blood N-CC in cultured podocytes was involved in the angio- pressure control. tensin II (Ang II)-induced reactive oxygen species pro- duction (4). Given that cilnidipine was previously found *Corresponding author. [email protected] to attenuate podocyte injury and proteinuria in a rat Published online in J-STAGE on July 21, 2012 (in advance) model of obesity and hypertension (4), then protection of doi: 10.1254/jphs.12075FP podocyte, cells that play an important role in the glomeru- 359 360 B Lei et al lar filtration barrier against plasma protein leakage into were harvested from 27-week-old animals. Half of the urine (4, 10), by N-CC inhibition may be the mechanism kidney was dissected immediately after blood collection behind the cilnidipine-induced reno-protection. On the by decapitation and was snap-frozen in liquid nitrogen other hand, cilnidipine is reported to dilate efferent arter- for measurement of renal Ang II content. ies and to suppress glomerular hypertension that could cause hyper-filtration and stimulate sclerotic changes Renal NE content (11 – 13). However, it is still unclear whether cilnidipine Extraction of NE from renal cortical tissue and subse- targets renal nerves or other cells to induce its reno-pro- quent processing were performed as follows. Briefly, tective effects in hypertensive subjects. pieces of renal cortex were homogenized in a 5-fold Therefore, the present study was conducted to sepa- volume of ice-cold saline containing 0.1 N HCl. After rately evaluate the reno-protective effects of cilnidipine, centrifugation (12,000 × g at 4°C) for 30 min, the super- specifically its actions on renal sympathetic nerves and natant was subjected to high-performance liquid chroma- other cells such as podocytes. We performed renal nerve tography with an amperometric detector (ECD-300; denervations in spontaneously hypertensive rats (SHR), Eicom, Kyoto; detection limit: 10 pg/mL) for measure- a model for essential hypertension that has been shown ment of NE. to express N-CC in podocytes (14), and assessed the ef- fects of cilnidipine in these animals compared to inner- Immunohistochemistry for desmin and N-CC vated rats. Immunohistochemistry for desmin, a marker of podo- cyte injury, and N-CC (Cav2.2 subunit) were performed Materials and Methods by using the Histofine Simple Stain MAX-PO MULTI (Nichirei Biosciences, Tokyo), as previously described Animals and experiment design (18, 19). Deparaffinized sections were incubated with All experimental procedures were performed accord- 0.1% hydrogen peroxide for 10 min for desmin or 0.3% ing to the guidelines for the care and use of animals, as hydrogen peroxide in methanol for 30 min for N-CC to established by the Kagawa University and the National block endogenous enzymes. For antigen retrieval, N-CC Research Council. Male SHR and Wistar-Kyoto rats sections were exposed to 0.1% Triton X for 30 min. After (WKY) were purchased from SLC (Shizuoka). Two blocking, sections were incubated with primary antibodies weeks prior to the initiation of the study (at 7 weeks of (anti-Human Desmin Mouse monoclonal antibody, D33, age), the right kidney was removed (uninephrectomized: 1:500, from DakoCytomation, Glostrup, Denmark; anti- UNX) through a small flank incision under pentobarbital Cav2.2 antibody, 1:100, from Alomone Labs, Jerusalem, anesthesia (50 mg/kg, i.p.). Denervation of the left kidney Israel) for 10 min (desmin) or 1 h (N-CC) at room tem- was accomplished by cutting all of the visible nerves perature. Antibodies were visualized with DAB substrate entering the renal hilus, stripping the renal artery and (DakoCytomation) and counterstained with hematoxylin vein of adventitia, and applying 10% phenol in 70% etha- (DakoCytomation). Sections that were incubated without nol to the vessels, as previously described (15). Denerva- primary antibodies were used as controls. Antibody- tion was confirmed by measuring renal norepinephrine positive areas were calculated from 20 randomly selected (NE) content at 27 weeks of age. microscope fields (× 200) in each section. Histological After recovery, UNX animals were divided into five analyses were performed using a color image analyzing experimental groups as follows: 1) vehicle (n = 14), 2) system (Image J) in a blinded manner. vehicle plus renal denervation (n = 15), 3) cilnidipine (50 mg/kg per day, p.o. via gavage, n = 10), 4) cilnidipine Histological examination plus renal denervation (50 mg/kg per day, p.o. via gav- Kidneys were fixed with 10% formalin (pH 7.4), em- age, n = 15), and 5) WKY (vehicle-administered, n = 10). bedded in paraffin, sectioned into 4-μm slices, and UNX-SHR and -WKY rats were fed a high-salt (HS: 4% stained with periodic acid – Schiff (PAS) reagent for ana- NaCl) diet (HS-UNX-SHR and HS-UNX-WKY) lyzing mesangial expansion and matrix protein accumu- throughout the experimental period to accelerate the lation. PAS staining was evaluated using light microscopy progression of renal injury (16, 17). (× 200). Positive glomerular sclerotic areas were counted Systolic blood pressure (SBP) was measured in con- using a photo-imaging system (Image J). scious rats by tail-cuff plethysmography (BP-98A; Softron, Tokyo); and 24-h urine samples were collected Cell culture condition and real-time PCR at 9, 12, 15, 18, 21, 24, and 27 weeks of age. All animals Conditionally immortalized mouse podocyte cell lines underwent a 12-h acclimatization period in metabolic were used for the cell culture study (20, 21). Cells were cages prior to urine collection. Blood and kidney samples maintained in RPMI 1640 (Sigma, St. Louis, MO, USA) Cilnidipine and Renal Sympathetic Nerves 361 supplemented with 10% fetal bovine serum (FBS) con- 45 taining 100 μg/ml penicillin and 100 μg/ml streptomycin 40 (without γ-interferon) at 37°C for 10 days. After that, 35 cells that achieved 60% confluence were first cultured 30 for 24 h in serum-free RPMI 1640 and then exposed to 25 vehicle, Ang II (100 nM), cilnidipine (10 μM), or ω-conotoxin (1 μM) for 24 h. The drug concentrations 20 selected were based on previous studies (22, 23). 15 N-CC (Cacna 1b gene) and glyceraldehyde-3-phos- 10 NE / tissue weight (ng/g) phate dehydrogenase (GAPDH) mRNA expression levels 5 N.D. N.D. were analyzed via real-time polymerase chain reaction 0 Vehicle Vehicle Cilnidipine Cilnidipine WKY (PCR) using a LightCycler FastStart DNA Master SYBR +DNX +DNX Green I kit (Applied Biosystems, Foster City, CA, USA), as previously described (24). The primer sequences for Fig. 1. Renal norepinephrine (NE) levels. Renal NE levels were undetectable in both cilnidipine-treated and untreated denervated Cacna 1b and transforming growth factor β1 (TGF-β1) SHR rats.
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