Vascular Endothelial Growth Factor and Placental Growth Factor in Conjunction with Vascular Endothelial Growth Factor Receptor-1 May Exert Dual Effects Within the Kidney and Brain in Patients with Type 2 Diabetes Mellitus and Normoalbuminuric Diabetic Kidney Disease

The kidney and the brain share similarities in terms of structure and haemodynamic regime. The aim of the study was to assess a potential correlation of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sFlt-1), and placental growth factor (PlGF) with biomarkers of podocyte damage, proximal tubular (PT) dysfunction, and endothelial dysfunction, as well as with cerebral vessels haemodynamic indices in neurologic asymptomatic type 2 DM patients. A cohort of 212 patients diagnosed with type 2 DM and 49 age- and gender-matched healthy controls were enrolled in the study. Parameters studied were urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin, podocalyxin), PT dysfunction (kidney injury molecule-1-KIM-1, N-acetyl-β-(D)-glucosaminidase-NAG), endothelial dysfunction (P-selectin), VEGF, sFlt-1, and PlGF. The cerebrovascular hemodynamic indices evaluated were intima–media thickness (IMT) in the common carotid arteries (CCAs), the pulsatility index (PI), and the resistivity index (RI) in the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs). Cerebrovascular reactivity (CVR) was assessed by the breath-holding index (BHI). In multivariable regression analysis, serum VEGF correlated directly with UACR, synaptopodin, NAG, serum P-selectin; serum sFlt-1 correlated directly with UACR, synaptopodin, podocalyxin, NAG, KIM-1; serum PlGF correlated negatively with eGFR and directly with UACR, synaptopodin, KIM-1. IMT-CCA correlated indirectly with eGFR and directly with UACR, serum P-selectin, and serum sFlt-1. The PI-ICAs correlated negatively with eGFR and positively with UACR, synaptopodin, serum P-selectin, and serum sFlt-1. The PI-MCAs correlated indirectly with eGFR and directly with synaptopodin, serum P-selectin, and serum sFlt-1. The RI-ICAs had a negative correlation with eGFR and a positive one with UACR, synaptopodin, NAG, KIM-1, urinary sFlt-1, and serum PlGF. The RI-MCAs displayed an indirect correlation with eGFR and a direct correlation with NAG, KIM-1, and serum sFlt-1. The BHT correlated directly with eGFR and negatively with serum P-selectin and serum PlGF. The study shows a significant association of VEGF, sFlt-1, and PlGF with biomarkers of podocyte injury, PT dysfunction, and endothelial dysfunction in early stages of DKD. These pro-angiogenic and anti-angiogenic factors correlated with cerebrovascular haemodynamic indices in neurologic asymptomatic type 2 DM, even in the normoalbuminuric stage of diabetic kidney disease.