Petrica Ligia, Gadalean Florica, Vlad Adrian, Muntean Danina Mirela, Vlad Daliborca, Dumitrascu Victor, Bob Flaviu, Milas Oana, Suteanu-Simulescu Anca, Glavan Mihaela, Ursoniu Sorin, Balint-Marcu Lavinia, Mogos-Stefan Maria, Ienciu Silvia, Cretu Octavian Marius, Popescu Roxana, Gluhovschi Cristina, Iancu Lavinia, Jianu Dragos Catalin
Division of Nephrology, Department of Internal Medicine II, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania.
Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania.
Int J Mol Sci. 2025 May 8;26(10):4481. doi: 10.3390/ijms26104481.
Diabetic kidney disease (DKD) displays a high prevalence of cardiovascular and cerebrovascular disease. Both the kidney and the brain share common pathogenic mechanisms, such as inflammation, endothelial dysfunction, oxidative stress, and mitochondrial dysfunction. The aim of this study was to establish a potential association of cerebral vessel remodeling and its related functional impairment with biomarkers of inflammation, oxidative stress, and mitochondrial dysfunction in the early stages of DKD in type 2 diabetes mellitus (DM) patients. A cohort of 184 patients and 39 healthy controls was assessed concerning serum and urinary stromal cell-derived factor-1 (SDF-1), P-selectin, advanced oxidation protein products (AOPPs), urinary synaptopodin, podocalyxin, kidney injury molecule-1 (KIM-1), and N-acetyl-β-(D)-glucosaminidase (NAG). The quantification of the mitochondrial DNA copy number (mtDNA-CN) and nuclear DNA (nDNA) in urine and peripheral blood was conducted using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Using TaqMan tests, the beta-2 microglobulin nuclear gene (B2M) and the cytochrome b (CYTB) gene, which encodes subunit 2 of NADH dehydrogenase (ND2), were evaluated. The MtDNA-CN is the ratio of mitochondrial DNA to nuclear DNA copies, ascertained through the examination of the CYTB/B2M and ND2/B2M ratios. The intima-media thickness (IMT) measurements of the common carotid arteries (CCAs), along with the pulsatility index (PI) and resistivity index (RI) of the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), were obtained through cerebral Doppler ultrasonography (US). Additionally, the breath-holding index (BHI) was also measured by cerebral Doppler US. PI-ICAs, PI-MCAs, CCAs-IMT, RI-MCAs, and RI-ICAs demonstrated direct relationships with SDF-1, P-selectin, AOPPs, urine mtDNA, podocalyxin, synaptopodin, NAG, and KIM-1 while showing indirect correlations with serum mtDNA and the eGFR. In contrast, the BHI had negative correlations with SDF-1, P-selectin, AOPPs, urine mtDNA, synaptopodin, podocalyxin, KIM-1, and NAG while showing direct associations with serum mtDNA and the eGFR. In conclusion, a causative association exists among SDF-1, P-selectin, and AOPPs, as well as mitochondrial dysfunction, in early diabetic kidney disease (DKD) and significant cerebrovascular alterations in patients with type 2 diabetes mellitus and normoalbuminuric DKD, with no neurological symptoms.
糖尿病肾病（DKD）中，心血管和脑血管疾病的患病率很高。肾脏和大脑具有共同的致病机制，如炎症、内皮功能障碍、氧化应激和线粒体功能障碍。本研究的目的是在2型糖尿病（DM）患者DKD的早期阶段，确定脑血管重塑及其相关功能损害与炎症、氧化应激和线粒体功能障碍生物标志物之间的潜在关联。对184例患者和39名健康对照者的血清和尿液中的基质细胞衍生因子-1（SDF-1）、P-选择素、晚期氧化蛋白产物（AOPPs）、尿足突蛋白、多配体蛋白聚糖、肾损伤分子-1（KIM-1）和N-乙酰-β-（D）-氨基葡萄糖苷酶（NAG）进行了评估。使用定量逆转录聚合酶链反应（qRT-PCR）对尿液和外周血中的线粒体DNA拷贝数（mtDNA-CN）和核DNA（nDNA）进行定量。使用TaqMan检测法评估β-2微球蛋白核基因（B2M）和编码烟酰胺腺嘌呤二核苷酸脱氢酶（ND2）亚基2的细胞色素b（CYTB）基因。MtDNA-CN是线粒体DNA与核DNA拷贝数的比值，通过检测CYTB/B2M和ND2/B2M比值来确定。通过脑多普勒超声（US）获得颈总动脉（CCA）的内膜中层厚度（IMT）测量值，以及颈内动脉（ICA）和大脑中动脉（MCA）的搏动指数（PI）和阻力指数（RI）。此外，脑多普勒超声还测量了屏气指数（BHI）。PI-ICA、PI-MCA、CCA-IMT、RI-MCA和RI-ICA与SDF-1、P-选择素、AOPPs、尿mtDNA、多配体蛋白聚糖、足突蛋白、NAG和KIM-1呈直接关系，而与血清mtDNA和估算肾小球滤过率（eGFR）呈间接相关。相比之下，BHI与SDF-1、P-选择素、AOPPs、尿mtDNA、足突蛋白、多配体蛋白聚糖、KIM-1和NAG呈负相关，而与血清mtDNA和eGFR呈直接关联。总之，在早期糖尿病肾病（DKD）以及2型糖尿病和正常白蛋白尿DKD且无神经症状的患者中，SDF-1、P-选择素和AOPPs以及线粒体功能障碍之间存在因果关联，且伴有显著的脑血管改变。
