Sex-specific molecular signature of mouse podocytes in homeostasis and in response to pharmacological challenge with rapamycin

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-09-15 DOI:10.1186/s13293-024-00647-7
Ola Al-Diab, Christin Sünkel, Eric Blanc, Rusan Ali Catar, Muhammad Imtiaz Ashraf, Hongfan Zhao, Pinchao Wang, Markus M. Rinschen, Raphaela Fritsche-Guenther, Florian Grahammer, Sebastian Bachmann, Dieter Beule, Jennifer A. Kirwan, Nikolaus Rajewsky, Tobias B. Huber, Dennis Gürgen, Angelika Kusch
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This work aimed at identifying sexual dimorphic molecular signatures of podocytes under physiological condition and pharmacologically challenged homeostasis with mechanistic target of rapamycin (mTOR) inhibition. mTOR is a crucial regulator involved in a variety of physiological and pathological stress responses in the kidney and inhibition of this pathway may therefore serve as a general stress challenger to get fundamental insights into sex differences in podocytes. The genomic ROSAmT/mG-NPHS2 Cre mouse model was used which allows obtaining highly pure podocyte fractions for cell-specific molecular analyses, and vehicle or pharmacologic treatment with the mTOR inhibitor rapamycin was performed for 3 weeks. Subsequently, deep RNA sequencing and proteomics were performed of the isolated podocytes to identify intrinsic sex differences. Studies were supplemented with metabolomics from kidney cortex tissues. Although kidney function and morphology remained normal in all experimental groups, RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways. Interestingly, rapamycin abolished prominent sex-specific clustering of podocyte gene expression and induced major changes only in male transcriptome. Several sex-biased transcription factors could be identified as possible upstream regulators of these sexually dimorphic responses. Concordant to transcriptomics, metabolomic changes were more prominent in males. Remarkably, high number of previously reported kidney disease genes showed intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. Our results highlight remarkable intrinsic sex-differences and sex-specific response patterns towards pharmacological challenged podocyte homeostasis which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. This work provides rationale and an in-depth database for novel targets to be tested in specific kidney disease models to advance with sex-specific treatment strategies. The global burden of chronic kidney diseases is rapidly increasing and is projected to become the fifth most common cause of years of life lost worldwide by 2040. Sexual dimorphism in kidney diseases and transplantation is well known, yet sex-specific therapeutic strategies are still missing. One reason is the lack of knowledge due to the lack of inclusion of sex as a biological variable in study designs. This work aimed at identification of molecular signatures of male and female podocytes, gate-keepers of the glomerular filtration barrier. 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Abstract

Sex differences exist in the prevalence and progression of major glomerular diseases. Podocytes are the essential cell-type in the kidney which maintain the physiological blood-urine barrier, and pathological changes in podocyte homeostasis are critical accelerators of impairment of kidney function. However, sex-specific molecular signatures of podocytes under physiological and stress conditions remain unknown. This work aimed at identifying sexual dimorphic molecular signatures of podocytes under physiological condition and pharmacologically challenged homeostasis with mechanistic target of rapamycin (mTOR) inhibition. mTOR is a crucial regulator involved in a variety of physiological and pathological stress responses in the kidney and inhibition of this pathway may therefore serve as a general stress challenger to get fundamental insights into sex differences in podocytes. The genomic ROSAmT/mG-NPHS2 Cre mouse model was used which allows obtaining highly pure podocyte fractions for cell-specific molecular analyses, and vehicle or pharmacologic treatment with the mTOR inhibitor rapamycin was performed for 3 weeks. Subsequently, deep RNA sequencing and proteomics were performed of the isolated podocytes to identify intrinsic sex differences. Studies were supplemented with metabolomics from kidney cortex tissues. Although kidney function and morphology remained normal in all experimental groups, RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways. Interestingly, rapamycin abolished prominent sex-specific clustering of podocyte gene expression and induced major changes only in male transcriptome. Several sex-biased transcription factors could be identified as possible upstream regulators of these sexually dimorphic responses. Concordant to transcriptomics, metabolomic changes were more prominent in males. Remarkably, high number of previously reported kidney disease genes showed intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. Our results highlight remarkable intrinsic sex-differences and sex-specific response patterns towards pharmacological challenged podocyte homeostasis which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. This work provides rationale and an in-depth database for novel targets to be tested in specific kidney disease models to advance with sex-specific treatment strategies. The global burden of chronic kidney diseases is rapidly increasing and is projected to become the fifth most common cause of years of life lost worldwide by 2040. Sexual dimorphism in kidney diseases and transplantation is well known, yet sex-specific therapeutic strategies are still missing. One reason is the lack of knowledge due to the lack of inclusion of sex as a biological variable in study designs. This work aimed at identification of molecular signatures of male and female podocytes, gate-keepers of the glomerular filtration barrier. Like cardiomyocytes, podocytes are terminally differentiated cells which are highly susceptible towards pathological challenges. Podocytes are the decisive cell-type of the kidney to maintain the physiological blood-urine barrier, and disturbances of their homeostasis critically accelerate kidney function impairment. By help of a genomic mouse model, highly purified podocytes were obtained from male and female mice with and without pharmacological challenge of the mechanistic target of rapamycin (mTOR) signaling pathway which is known to be deregulated in major kidney diseases. Deep RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. Remarkably, high number of previously reported kidney disease genes showed so far unknown intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. Our work provides an in-depth database for novel targets to be tested in kidney disease models to advance with sex-specific treatment strategies.
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小鼠荚膜细胞在体内平衡和雷帕霉素药理作用下的性别特异性分子特征
主要肾小球疾病的发病率和进展存在性别差异。荚膜细胞是肾脏中维持生理血尿屏障的重要细胞类型,荚膜细胞稳态的病理变化是肾功能受损的关键加速因素。然而,荚膜细胞在生理和应激条件下的性别特异性分子特征仍然未知。mTOR是参与肾脏各种生理和病理应激反应的关键调节因子,因此抑制该通路可作为一种通用的应激挑战因子,从根本上揭示荚膜细胞的性别差异。采用基因组ROSAmT/mG-NPHS2 Cre小鼠模型可获得高纯度的荚膜细胞碎片,用于细胞特异性分子分析。随后,对分离的荚膜细胞进行了深度 RNA 测序和蛋白质组学分析,以确定内在的性别差异。研究还辅以肾皮质组织的代谢组学。虽然所有实验组的肾功能和形态都保持正常,但 RNA 测序、蛋白质组学和代谢组学发现,线粒体、翻译和结构转录本的表达水平、蛋白质丰度和代谢途径的调控都存在强烈的内在性别差异。有趣的是,雷帕霉素消除了荚膜细胞基因表达的突出性别特异性集群,只诱导男性转录组发生重大变化。几种有性别偏见的转录因子可能是这些性别二态反应的上游调节因子。与转录组学一致,代谢组学的变化在雄性中更为显著。值得注意的是,大量以前报道过的肾脏疾病基因显示了内在的性别二态性和/或对mTOR抑制的不同反应模式。我们的研究结果突显了显著的内在性别差异和对药物挑战荚膜细胞稳态的特异性反应模式,这可能从根本上导致肾脏疾病易感性和进展的性别差异。这项工作为在特定肾病模型中测试新靶点提供了理论依据和深入的数据库,以推进性别特异性治疗策略。慢性肾脏疾病给全球造成的负担正在迅速增加,预计到 2040 年将成为导致全球寿命损失的第五大常见病因。肾脏疾病和移植中的性别二形性已广为人知,但仍缺乏针对不同性别的治疗策略。原因之一是在研究设计中没有将性别作为一个生物变量纳入其中,从而导致知识的匮乏。这项研究旨在鉴定肾小球滤过屏障的守门人--男性和女性荚膜细胞的分子特征。与心肌细胞一样,荚膜细胞也是终末分化的细胞,极易受到病理挑战的影响。荚膜细胞是肾脏维持生理血尿屏障的决定性细胞类型,其平衡紊乱会严重加速肾功能损伤。在基因组小鼠模型的帮助下,研究人员从接受或未接受雷帕霉素机制靶标(mTOR)信号通路药物挑战的雌雄小鼠体内获得了高度纯化的荚膜细胞。深度 RNA 测序、蛋白质组学和代谢组学发现,线粒体、翻译和结构转录本的表达水平、蛋白质丰度和代谢通路的调控存在强烈的内在性别差异,这可能从根本上导致肾脏疾病易感性和进展的性别差异。值得注意的是,之前报道的大量肾病基因显示出迄今未知的内在性双态性和/或对 mTOR 抑制的不同反应模式。我们的工作提供了一个深入的数据库,用于在肾脏疾病模型中测试新的靶点,以推进性别特异性治疗策略。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
期刊最新文献
Sex differences in the human brain related to visual motion perception. A call for inclusive research, policies, and leadership to close the global women's health gap. Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment. Sex dimorphism and tissue specificity of gene expression changes in aging mice. The Four Core Genotypes mouse model: evaluating the impact of a recently discovered translocation.
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