瘦素受体在肾小管中的表达是稀疏的,但与瘦素依赖性肾基因的表达和功能有关。

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-06-01 Epub Date: 2023-04-27 DOI:10.1152/ajprenal.00279.2022
Young Chul Kim, Hadi Fattah, Yiling Fu, Josselin Nespoux, Volker Vallon
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引用次数: 0

摘要

瘦素通过在中枢和外周组织中表达的瘦素受体调节能量平衡,但对瘦素敏感的肾脏基因和小管瘦素受体(Lepr)在高脂肪饮食(HFD)反应中的作用知之甚少。对麻风病毒剪接变异A、B和C的定量RT-PCR分析显示,小鼠肾皮质和髓质中麻风病毒剪接变异A、B和C的比例为~ 100:10:1,髓质中麻风病毒剪接变异的水平高出约10倍。在ob/ob小鼠中替换瘦素6天,减少了贪食、高血糖和蛋白尿,与肾脏中糖酵解、糖异生、氨基酸合成和meggalin分子标记的mRNA表达正常化有关。在ob/ob小鼠中使瘦素正常化7小时并没有使高血糖或蛋白尿正常化。Lepr的小管敲除[Pax8-Lepr敲除(KO)]和原位杂交显示,与内皮细胞相比,小管细胞中Lepr mRNA的含量较少。然而,Pax8-Lepr KO小鼠的肾脏重量较低。此外,虽然hfd诱导的高瘦素血症、肾脏重量和肾小球滤过率的增加以及适度的降血压效果与对照组相似,但它们显示出蛋白尿的缓慢上升。在ob/ob小鼠中使用Pax8-Lepr KO和瘦素替代,鉴定乙酰乙酰辅酶a合成酶和gremlin 1分别是瘦素增加和减少的小管麻风敏感基因。综上所述,瘦素缺乏可能通过影响肾巨高蛋白表达的全身代谢作用增加白蛋白尿,而高瘦素血症可能通过直接的小管麻风效应诱导白蛋白尿。Lepr变异和新型管状Lepr/乙酰乙酰辅酶a合成酶/gremlin 1轴的意义仍有待确定。这项研究为瘦素受体剪接变异的肾脏基因表达、瘦素敏感的肾脏基因表达以及瘦素受体在肾小管细胞中对饮食诱导的高瘦素血症和肥胖(包括蛋白尿)的反应提供了新的见解。
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Expression of leptin receptor in renal tubules is sparse but implicated in leptin-dependent kidney gene expression and function.

Leptin regulates energy balance via leptin receptors expressed in central and peripheral tissues, but little is known about leptin-sensitive kidney genes and the role of the tubular leptin receptor (Lepr) in response to a high-fat diet (HFD). Quantitative RT-PCR analysis of Lepr splice variants A, B, and C revealed a ratio of ∼100:10:1 in the mouse kidney cortex and medulla, with medullary levels being ∼10 times higher. Leptin replacement in ob/ob mice for 6 days reduced hyperphagia, hyperglycemia, and albuminuria, associated with normalization of kidney mRNA expression of molecular markers of glycolysis, gluconeogenesis, amino acid synthesis, and megalin. Normalization of leptin for 7 h in ob/ob mice did not normalize hyperglycemia or albuminuria. Tubular knockdown of Lepr [Pax8-Lepr knockout (KO)] and in situ hybridization revealed a minor fraction of Lepr mRNA in tubular cells compared with endothelial cells. Nevertheless, Pax8-Lepr KO mice had lower kidney weight. Moreover, while HFD-induced hyperleptinemia, increases in kidney weight and glomerular filtration rate, and a modest blood pressure lowering effect were similar compared with controls, they showed a blunted rise in albuminuria. Use of Pax8-Lepr KO and leptin replacement in ob/ob mice identified acetoacetyl-CoA synthetase and gremlin 1 as tubular Lepr-sensitive genes that are increased and reduced by leptin, respectively. In conclusion, leptin deficiency may increase albuminuria via systemic metabolic effects that impinge on kidney megalin expression, whereas hyperleptinemia may induce albuminuria by direct tubular Lepr effects. Implications of Lepr variants and the novel tubular Lepr/acetoacetyl-CoA synthetase/gremlin 1 axis remain to be determined.NEW & NOTEWORTHY This study provides new insights into kidney gene expression of leptin receptor splice variants, leptin-sensitive kidney gene expression, and the role of the leptin receptor in renal tubular cells for the response to diet-induced hyperleptinemia and obesity including albuminuria.

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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
期刊最新文献
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