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 disease. Normoalbuminuric subjects are considered at no cardiorenal risk in clinical practice, and molecular changes underlying early development are unclear. To decipher subjacent mechanisms, we stratified the normoalbuminuria condition. A total of 37 hypertensive patients under chronic renin–angiotensin system (RAS) suppression with ACR values in the normoalbuminuria range were included and classified as control (C) (ACR < 10 mg/g) and high-normal (HN) (ACR = 10–30 mg/g). Target metabolomic analysis was carried out by liquid chromatography and mass spectrometry to investigate the role of the 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 was carried out. Nine metabolites showed significantly altered abundance in HN versus C, and urinary FFAs and FABP1 increased in HN group, pointing to dysregulation in the tricarboxylic acid cycle (TCA) cycle and fatty acids β-oxidation. We showed here how cardiorenal metabolites associate with albuminuria, already in the normoalbuminuric range, evidencing early renal damage at a tubular level and suggesting increased β-oxidation to potentially counteract fatty acids overload in the HN range.

Donor liquid biopsy and outcomes in kidney transplantation

“…Thus specific changes in tubular function in living donors could predict the risk of lower GFR after transplantation not identified by pre-transplant assessment of donor glomerular function, supporting the study of other makers of tubular function or injury. In agreement with this finding, we recently demonstrated that early subclinical kidney injury resulting in defective tubular reabsorption is reflected in protein and metabolic alterations in urine that identified normoalbuminuric subjects within the high-normal range (albumin:creatinine ratio 10–30 mg/g) that have a higher risk of cardiovascular disease and renal function decline [ 42 , 43 ]. The tricarboxylic acid cycle was identified as a key biological pathway in urine of high-risk normoalbuminuric subjects and it is also altered in pre-implantation biopsies taken from kidneys that displayed low function 24 months post-transplantation [ 26 ].…”

An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats

“…In contrast to weight loss caused by diet, the energy expenditure during weight loss caused by the SGLT2i did not decrease ( Ferrannini et al, 2015 ), which may be due to increased lipid oxidation ( Osataphan et al, 2019 ). With the reduction of glucose and its utilization, alternative fuels must be used to provide the TCA cycle during fasting, such as amino acids, fatty acids, or ketone bodies ( Akram, 2014 ; Rui, 2014 ; Santiago-Hernandez et al, 2021 ). Here, we found that BCAA in the myocardium was only slightly reduced after CANA treatment, and the expression of regulatory proteins did not change significantly, suggesting that there was no significant increase in amino acid catabolism.…”

Novel Targets and Potential Mechanisms of Mizuhopecten yessoensis‐Derived Tripeptide NCW as Antihypertensive Peptides

“…Fatty acids conjugated to albumin enter the proximal tubule cells via the uptake of membrane proteins such as FABP or CD36 and are transformed into acyl-CoA, which is subjected to mitochondrial 𝛽-oxidation to generate acetyl-CoA for the TCA cycle, along with the production of ATP. [8,9] Elevated expression of FABP1 could drive the 𝛽-oxidation of fatty acids. Thus, tripeptide NCW administration enhanced the glycolysis, TCA cycle, and fatty acids 𝛽-oxidation.…”