Podocyte cell-specific Npr1 is required for blood pressure and renal homeostasis in male and female mice: role of sex-specific differences.

IF 2.5 4区 生物学 Q3 CELL BIOLOGY
Physiological genomics Pub Date : 2024-10-01 Epub Date: 2024-08-05 DOI:10.1152/physiolgenomics.00137.2023
Chandramohan Ramasamy, Kandasamy Neelamegam, Samivel Ramachandran, Huijing Xia, Daniel R Kapusta, Farhad R Danesh, Kailash N Pandey
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引用次数: 0

Abstract

Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase A/natriuretic peptide receptor A (GC-A/NPRA), stimulating natriuresis and diuresis and reducing blood pressure (BP), but the role of ANP/NPRA signaling in podocytes (highly specialized epithelial cells covering the outer surfaces of renal glomerular capillaries) remains unclear. This study aimed to determine the effect of conditional deletion of podocyte-specific Npr1 (encoding NPRA) gene knockout (KO) in male and female mice. Tamoxifen-treated wild-type control (PD Npr1 f/f; WT), heterozygous (PD-Cre-Npr1 f/+; HT), and KO (PD-Cre-Npr1 f/-) mice were fed a normal-, low-, or high-salt diet for 4 wk. Podocytes isolated from HT and KO male and female mice showed complete absence of Npr1 mRNA and NPRA protein compared with WT mice. BP, plasma creatinine, plasma sodium, urinary protein, and albumin/creatinine ratio were significantly increased, whereas plasma total protein, albumin, creatinine clearance, and urinary sodium levels were significantly reduced in the HT and KO male and female mice compared with WT mice. These changes were significantly greater in males than in females. On a normal-salt diet, glomerular filtration rate was significantly decreased in PD Npr1 HT and KO male and female mice compared with WT mice. Immunofluorescence of podocin and synaptopodin was also significantly reduced in HT and KO mice compared with WT mice. These observations suggest that in podocytes, ANP/NPRA signaling may be crucial in the maintenance and regulation of glomerular filtration and BP and serve as a biomarker of renal function in a sex-dependent manner.NEW & NOTEWORTHY Our results demonstrate that the podocyte-specific deletion of Npr1 showed increased blood pressure (BP) and altered biomarkers of renal functions, with greater magnitudes in animals fed a high-salt diet in a sex-dependent manner. The results suggest a direct and sex-dependent effect of Npr1 ablation in podocytes on the regulation of BP and renal function and reveal that podocytes may be considered an important target for the ANP-BNP/NPRA/cGMP signaling cascade.

荚膜细胞特异性 Npr1 是雄性和雌性小鼠血压和肾脏稳态所必需的:性别差异的作用。
心房钠尿肽和脑钠尿肽(ANP和BNP)与鸟苷酸环化酶-A/钠尿肽受体-A(GC-A/NPRA)结合,刺激利尿和利尿并降低血压(BP),但ANP/NPRA信号传导在荚膜细胞(覆盖肾小球毛细血管外表面的高度特化的上皮细胞)中的作用仍不清楚。本研究旨在确定雌雄小鼠荚膜细胞(PD)特异性 Npr1(编码 NPRA)基因敲除(KO)条件性缺失的影响。用正常、低盐或高盐饮食喂养经他莫昔芬处理的野生型对照组(PD Npr1 f/f; WT)、杂合子(PD-Cre-Npr1 f/+; HT)和基因敲除(PD-Cre-Npr1 f/-; KO)小鼠 4 周。与 WT 小鼠相比,从 HT 和 KO 雌雄小鼠体内分离出的荚膜细胞完全没有 Npr1 mRNA 和 NPRA 蛋白。与 WT 小鼠相比,HT 和 KO 雌雄小鼠的血压、血浆肌酐、血浆钠、尿蛋白和白蛋白/肌酐比值显著升高,而血浆总蛋白、白蛋白、肌酐清除率和尿钠水平显著降低。雄性小鼠的这些变化明显大于雌性小鼠。与 WT 小鼠相比,在正常盐饮食中,PD Npr1 HT 和 KO 雌雄小鼠的肾小球滤过率(GFR)明显下降。与 WT 小鼠相比,HT 和 KO 小鼠中 podocin 和 synaptopodin 的免疫荧光也明显降低。这些观察结果表明,在荚膜细胞中,ANP/NPRA 信号传导可能是维持和调节肾小球滤过和血压的关键,并以性别依赖的方式作为肾功能的生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Physiological genomics
Physiological genomics 生物-生理学
CiteScore
6.10
自引率
0.00%
发文量
46
审稿时长
4-8 weeks
期刊介绍: The Physiological Genomics publishes original papers, reviews and rapid reports in a wide area of research focused on uncovering the links between genes and physiology at all levels of biological organization. Articles on topics ranging from single genes to the whole genome and their links to the physiology of humans, any model organism, organ, tissue or cell are welcome. Areas of interest include complex polygenic traits preferably of importance to human health and gene-function relationships of disease processes. Specifically, the Journal has dedicated Sections focused on genome-wide association studies (GWAS) to function, cardiovascular, renal, metabolic and neurological systems, exercise physiology, pharmacogenomics, clinical, translational and genomics for precision medicine, comparative and statistical genomics and databases. For further details on research themes covered within these Sections, please refer to the descriptions given under each Section.
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