TCA Cycle and Fatty Acids Oxidation Reflect Early Cardiorenal Damage in Normoalbuminuric Subjects with Controlled Hypertension

Abstract

Moderately increased albuminuria, defined by an albumin to creatinine ratio(ACR) > 30 mg/g,is an indicator of subclinical organ damage associated with a higher risk of cardiovascular and renal dis-ease. Normoalbuminuric subjects are considered at no cardiorenal risk in clinical practice, and molecularchanges underlying early development are unclear. To decipher subjacent mechanisms, we stratifiedthe normoalbuminuria condition. A total of 37 hypertensive patients under chronic renin–angiotensinsystem (RAS) suppression with ACR values in the normoalbuminuria range were included and classifiedas control (C) (ACR < 10 mg/g) and high-normal (HN) (ACR = 10–30 mg/g). Target metabolomicanalysis was carried out by liquid chromatography and mass spectrometry to investigate the role ofthe cardiorenal risk urinary metabolites previously identified. Besides this, urinary free fatty acids (FFAs),fatty acid binding protein 1 (FABP1) and nephrin were analyzed by colorimetric and ELISA assays.A Mann–Whitney test was applied, ROC curves were calculated and Spearman correlation analysis wascarried out. Nine metabolites showed significantly altered abundance in HN versus C, and urinary FFAsand FABP1 increased in HN group, pointing to dysregulation in the tricarboxylic acid cycle (TCA) cycleand fatty acidsβ-oxidation. We showed here how cardiorenal metabolites associate with albuminuria,already in the normoalbuminuric range, evidencing early renal damage at a tubular level and suggestingincreasedβ-oxidation to potentially counteract fatty acids overload in the HN range.