Amaral Andressa G, da Silva Camille C C, Serna Julian D C, Honorato-Sampaio Kinulpe, Freitas Jéssica A, Duarte-Neto Amaro N, Bloise Antonio C, Cassina Laura, Yoshinaga Marcos Y, Chaves-Filho Adriano B, Qian Feng, Miyamoto Sayuri, Boletta Alessandra, Bordin Silvana, Kowaltowski Alicia J, Onuchic Luiz F
Disciplinas de Nefrologia e Medicina Molecular, Departamento de Clínica Médica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
Biochim Biophys Acta Mol Basis Dis. 2022 Jun 1;1868(6):166371. doi: 10.1016/j.bbadis.2022.166371. Epub 2022 Feb 24.
Cardiovascular manifestations account for marked morbi-mortality in autosomal dominant polycystic kidney disease (ADPKD). Pkd1- and Pkd2-deficient mice develop cardiac dysfunction, however the underlying mechanisms remain largely unclear. It is unknown whether impairment of polycystin-1 cleavage at the G-protein-coupled receptor proteolysis site, a significant ADPKD mutational mechanism, is involved in this process. We analyzed the impact of polycystin-1 cleavage on heart metabolism using Pkd1 mice, a model unable to cleave this protein and with early cardiac dysfunction. Pkd1 hearts showed lower levels of glucose and amino acids and higher lipid levels than wild-types, as well as downregulation of p-AMPK, p-ACCβ, CPT1B-Cpt1b, Ppara, Nppa and Acta1. These findings suggested decreased fatty acid β-oxidation, which was confirmed by lower oxygen consumption by Pkd1 isolated mitochondria using palmitoyl-CoA. Pkd1 hearts also presented increased oxygen consumption in response to glucose, suggesting that alternative substrates may be used to generate energy. Pkd1 hearts displayed a higher density of decreased-size mitochondria, a finding associated with lower MFN1, Parkin and BNIP3 expression. These derangements were correlated with increased apoptosis and inflammation but not hypertrophy. Notably, Pkd1 neonate cardiomyocytes also displayed shifts in oxygen consumption and p-AMPK downregulation, suggesting that, at least partially, the metabolic alterations are not induced by kidney dysfunction. Our findings reveal that disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice, expanding the understanding of heart dysfunction associated with Pkd1 deficiency and likely with human ADPKD.
心血管表现是常染色体显性多囊肾病（ADPKD）中显著的致病和致死因素。Pkd1和Pkd2基因敲除小鼠会出现心脏功能障碍，但其潜在机制仍不清楚。目前尚不清楚在G蛋白偶联受体蛋白水解位点上多囊蛋白-1的裂解受损（这是一种重要的ADPKD突变机制）是否参与了这一过程。我们使用Pkd1小鼠分析了多囊蛋白-1裂解对心脏代谢的影响，Pkd1小鼠是一种无法裂解该蛋白且早期出现心脏功能障碍的模型。与野生型相比，Pkd1小鼠心脏中的葡萄糖和氨基酸水平较低，脂质水平较高，同时p-AMPK、p-ACCβ、CPT1B-Cpt1b、Ppara、Nppa和Acta1的表达下调。这些发现提示脂肪酸β氧化减少，使用棕榈酰辅酶A对Pkd1分离的线粒体进行检测，结果显示其耗氧量降低，证实了这一点。Pkd1小鼠心脏对葡萄糖的反应也表现出耗氧量增加，这表明可能使用其他底物来产生能量。Pkd1小鼠心脏中尺寸减小的线粒体密度更高，这一发现与MFN1、Parkin和BNIP3表达降低有关。这些紊乱与细胞凋亡和炎症增加相关，但与肥大无关。值得注意的是，Pkd1新生心肌细胞也表现出耗氧量的变化和p-AMPK下调，这表明至少部分代谢改变不是由肾功能障碍引起的。我们的研究结果表明，多囊蛋白-1裂解的破坏会导致小鼠心脏代谢重新布线，这加深了我们对与Pkd1缺乏相关以及可能与人类ADPKD相关的心脏功能障碍的理解。
