nefrНефрологияNephrology (Saint-Petersburg)1561-62742541-9439Pavlov First Saint-Petersburg State Medical University10.36485/1561-6274-2020-24-4-93-101nefr-1864Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИ. ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL ARTICLES. EXPERIMENTAL INVESTIGATIONПовышенная экспрессия TRPC6 в кардиомиоцитах как один из механизмов гипертрофии миокарда при дисфункции почекCardiomyocyte TRPC6 overexpression as one of the myocardial hypertrophy mechanisms in chronic kidney dysfunctionhttps://orcid.org/0000-0003-1969-1959БогдановаЕ. О.BogdanovaE. O.

Богданова Евдокия Олеговна, канд. биол. наук, лаборатория биохимического гомеостаза

197022, Санкт-Петербург, ул. Л. Толстого, д. 17, корп. 54

Тел.: (812) 338-69-31

Bogdanova Evdokia PhD, Biochemical Homeostasis

197022, St. Petersburg, L. Tolstoy st., 17, build. 54

Phone: (812)338-69-31

bogdanova@gmail.comhttps://orcid.org/0000-0002-5595-3832СеменоваН. Ю.SemenovaN. Yu.

Семенова Наталья Юрьевна, канд. биол. наук, Научно-исследовательский отдел патоморфологии

197341, Санкт-Петербург, ул. Аккуратова, д. 2

Тел.: (812)338-69-31

Natalia Y. Semenova, PhD

197341, St. Petersburg, Akkuratova st., 2

Phone: (812)338-69-31

natyciel87@gmail.comhttps://orcid.org/0000-0002-7532-2405БересневаО. Н.BeresnevaO. N.

Береснева Ольга Николаевна, канд. биол. наук, лаборатория клинической физиологии почки

197022, Санкт-Петербург, ул. Л. Толстого, д. 17, корп. 54

Тел.: (812)338-69-31

Olga N. Beresneva PhD, Laboratory of Kidney Clinical Physiology

197022, St. Petersburg, L. Tolstoy st., 17, build. 54

Phone: (812)338-69-31

beresnevaolga@list.ruhttps://orcid.org/0000-0001-7265-7392ГалкинаО. В.GalkinaO. V.

Галкина Ольга Владимировна, канд. биол. наук, лаборатория биохимического гомеостаза

197022, Санкт-Петербург, ул. Л. Толстого, д. 17, корп. 54

Тел.: (812) 338-69-31

Olga V. Galkina PhD, Laboratory of Biochemical Homeostasis, head

197022, St. Petersburg, L. Tolstoy st., 17, build. 54

Phone: (812)338-69-31

ovgalkina@mail.ruhttps://orcid.org/0000-0001-8491-7016ЗубинаИ. М.ZubinaI. M.

Зубина Ирина Михайловна, канд. биол. наук, лаборатория биохимического гомеостаза

197022, Санкт-Петербург, ул. Л. Толстого, д. 17, корп. 54

Тел.: (812)338-69-31

Irina M. Zubina PhD, Laboratory of Biochemical Homeostasis

197022, St. Petersburg, L. Tolstoy st., 17, build. 54

Phone: (812)338-69-31

zubina@list.ruhttps://orcid.org/0000-0003-0188-5173ИвановаГ. Т.IvanovaG. T.

Иванова Галина Тажимовна, канд. биол. наук, лаборатория физиологии сердечно-сосудистой и лимфатической системы

199034, Санкт-Петербург, наб. Макарова, д. 6

Тел.: (812)328-11-01

Galina T. Ivanova PhD, Physiology of the Russian Academy of Sciences Laboratory of cardiovascular and lymphatic systems physiology

199034, St. Petersburg, seafront Makarova, build. 6

Phone: (812)328-11-01

pavlov.institute@infran.ruhttps://orcid.org/0000-0002-4526-8671ПарастаеваМ. М.ParastaevaM. M.

Парастаева Марина Магрезовна, канд. биол. наук, лаборатория клинической физиологии почки

197022, Санкт-Петербург, ул. Л. Толстого, д. 17, корп. 54

Тел.: (812) 338-69-01

Marina M. Parastaeva PhD, Laboratory of Kidney Clinical Physiology

197022, St. Petersburg, L. Tolstoy st., 17, build. 54

Phone: (812)338-69-01

beresnevaolga@list.ruhttps://orcid.org/0000-0002-7179-5520ДобронравовВ. А.DobronravovV. A.

Проф. Добронравов Владимир Александрович, д-р мед. наук, заместитель директора

197022, Санкт-Петербург, ул. Л. Толстого, д. 17, корп. 54

Тел.: (812)338-69-01

Prof. Vladimir A. Dobronravov, MD, PhD, DSc, Vice Director

197022, St. Petersburg, L. Tolstoy st., 17, build. 54

Phone: (812)338-69-01

dobronravov@nephrolog.ruНаучно-исследовательский институт нефрологии, Научно-клинический исследовательский центр, Первый Санкт-Петербургский медицинский университет им. акад. И.П. ПавловаРоссияInstitute of Nephrology Pavlov First Saint Petersburg State Medical UniversityRussian FederationНаучно-исследовательский отдел патоморфологии, Центр доклинических и трансляционных исследований, Институт экспериментальной медицины, Национальный медицинский исследовательский центр им. В. А. АлмазоваРоссияResearch Department of Pathomorphology, Center for Preclinical and Translational Research, Institute of Experimental Medicine, Almazov National Medical Research CenterRussian Federation20202606202024493101Copyright © Богданова Е.О., Семенова Н.Ю., Береснева О.Н., Галкина О.В., Зубина И.М., Иванова Г.Т., Парастаева М.М., Добронравов В.А., 20202020Богданова Е.О., Семенова Н.Ю., Береснева О.Н., Галкина О.В., Зубина И.М., Иванова Г.Т., Парастаева М.М., Добронравов В.А.Bogdanova E.O., Semenova N.Y., Beresneva O.N., Galkina O.V., Zubina I.M., Ivanova G.T., Parastaeva M.M., Dobronravov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nephrolog.ru/jour/article/view/1864

ВВЕДЕНИЕ. Klotho – трансмембранный и циркулирующий протеин, преимущественно синтезируемый почками. Дефицит Klotho характерен для хронической болезни почек (ХБП), как и гипертрофии миокарда (ГМ). Кардиопротективное действие белка Klotho обусловлено негативной регуляцией разнообразных стрессовых сигналов, приводящих к активации гипертрофического внутриклеточного пути кальциневрин (CaN)/ NFAT в миокарде. Действие Klotho предположительно может быть опосредовано модуляцией Са2+-каналов и/или факторов Foxo, существенных для передачи сигналов CaN. ЦЕЛЬ: исследовать активность сигнального пути кальциневрин/NFAT в миокарде и определить механизмы его регуляции при снижении Klotho, обусловленном экспериментальной ХБП у спонтанно-гипертензивных крыс (SHR). МАТЕРИАЛ И МЕТОДЫ. Для моделирования ХБП выполняли нефрэктомию (НЭ) 3/4 или 5/6 объема органа у крыс линии SHR. Контролем служили ложнооперированные (ЛО) SHR и крысы линии Вистар Киото (WKY). У всех животных измеряли систолическое артериальное давление, рассчитывали индекс массы миокарда – ИММ, клиренс креатинина, измеряли диаметр кардиомиоцитов (КМЦ), уровни Klotho в сыворотке крови (ИФА) и почке (ИГХ), анализировали экспрессию кальциневрина (ИГХ, ПЦР), транскрипционного фактора NFAT (ИГХ), Ca2+-каналов TRPC6 (ИГХ), экспрессию FOXO3A (ПЦР) и фосфорилированных Foxo1/3/4 (ИГХ) в миокарде. Выраженность экспрессии кальциневрина и TRPC6 в миокарде, Klotho в почке рассчитывали как долю площади специфического продукта ИГХ-реакции от площади поля зрения. При анализе экспрессии NFAT рассчитывали долю позитивно окрашенных ядер от количества ядер в поле зрения. Измерения выполняли в 10 полях зрения для каждого гистологического препарата. РЕЗУЛЬТАТЫ. Полученные модели соответствовали начальным стадиям ХБП. У крыс с НЭ наблюдали увеличение ИММ (р=0,005), диаметра КМЦ (р=0,002). Почечная экспрессия Klotho (p=0,019) и концентрация Klotho в сыворотке крови (p=0,020) были ниже при НЭ. ИММ и толщина КМЦ были независимо ассоциированы с уровнем белка Klotho почечного происхождения (β=–0,38±0,16, p=0,026, β=–0,64±0,14, p<0,001 соответственно). НЭ и системная гипертензия сопровождались увеличением экспрессии гена кальциневрина (p=0,005) и кальциневрина в цитоплазме КМЦ (p=0,004), количества NFAT-позитивных ядер (p=0,007), ростом экспрессии гена FOXO3A (p<0,001) при отсутствии накопления фосфорилированных форм Foxo1/3/4 в цитоплазме КМЦ. Для крыс SHR было характерно выраженное позитивное ИГХ-окрашивание TRPC6 по сравнению с WKY (p=0,004). Экспрессия кальциневрина и TRPC6 изменялись сонаправленно (r=0,69, p<0,001), и оба этих показателя были ассоциированы с уровнем Klotho (кальциневрин vs Klotho в почке, r=–0,73, p<0,001; TRPC6 vs Klotho в сыворотке, r=-0,43, p=0,025). ЗАКЛЮЧЕНИЕ. Формирующийся на начальных стадиях ХБП системный дефицит белка Klotho ассоциирован с увеличением экспрессии Са2+-каналов кардиомиоцитов и активацией гипертрофического сигнального пути кальциневрин/NFAT в кардиомиоцитах.

BACKGROUND. Klotho is a transmembrane and circulating protein primarily synthesized by the kidney. Klotho deficiency characterizes chronic kidney disease (CKD), as myocardial hypertrophy (GM). The cardioprotective effect of the Klotho protein is due to the negative regulation of a variety of stress signals, leading to the activation of the hypertrophic intracellular signaling pathway calcineurin (CaN) / NFAT in the myocardium. The effect of Klotho may presumably be mediated by the modulation of Ca2 + channels and / or Foxo factors essential for CaN signaling. THE AIM: to study the activity of CaN/ NFAT signaling pathway in the myocardium and to determine the molecular mechanisms of its regulation in conditions of Klotho level decrease in spontaneous hypertensive rats (SHR) with experimental CKD. MATERIAL AND METHODS. The experimental model of CKD was 3/4 or 5/6 nephrectomy (Nx) in SHR. Sham-operated (SO) SHR, and Wistar Kyoto rats (WKY) were used as controls. In all animals were measured systolic blood pressure, myocardial mass index – MMI, creatinine clearance, cardiomyocyte (CM) diameter, Klotho levels in serum (ELISA) and kidney (IHC), myocardial expression of calcineurin (IHC, PCR), transcription factor NFAT (IHC), TRPC6 (IHC), FOXO3A (PCR) and phosphor-Foxo1/3/4 (IHC). The tissue expressions of calcineurin, TRPC6, and Klotho were calculated as the IHC specific product area to the field of view ratio. NFAT expression was evaluated as the positively stained nuclei to the number of nuclei ratio in the field of view. Measurements were performed in 10 fields of view for each histology slide. RESULTS. The model has corresponded to the initial stages of CKD. The increase in MMI (p = 0.005) and CM diameter (p = 0.002) were observed compared in Nx rats to SO. Renal Klotho expression (p < 0.001), and serum Klotho level (p = 0.019) were lower in the Nx. In multiple linear regression analyzes, the values of MMI and CM thickness were independently associated with the level of renal Klotho protein (β = -0.38 ± 0.16, p = 0.026, β = -0.64 ± 0.14, p <0.001, respectively). Nx and systemic hypertension were accompanied by an increase in the expression of the calcineurin gene (p = 0.005) and cytoplasmic calcineurin in CM (p = 0.004), the number of NFAT-positive nuclei (p = 0.007), and an increase in the expression of the FOXO3A gene (p <0.001) in the absence of accumulation of phosphorylated Foxo1/3/4 in CM cytoplasm. SHR rats were characterized by positive IHC staining for TRPC6 compared to WKY (p = 0.004). The expression of calcineurin and TRPC6 varied co-directionally (r = 0.69, p <0.001), and both of these indicators were associated with the Klotho levels (calcineurin vs Klotho in the kidney, r = -0.73, p <0.001; TRPC6 vs Klotho in serum, r = -0.43, p = 0.025). CONCLUSION. The development of Klotho deficiency on early-stage CKD is associated with the expression of transient Ca2+ channels TRPC6 and activation of the calcineurin / NFAT hypertrophic signaling pathway in cardiomyocytes.

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The authors declare that there are no conflicts of interest present.