ApoD and ApoA-IV, novel proteomic components in HDL of diabetic kidney disease without dialysis

Abstract Background and aims: Diabetic kidney disease (DKD) is associated with lipid derangements worsening kidney function and enhancing cardiovascular (CVD) risk. The management of dyslipidemia, hypertension and other traditional risk factors does not completely prevent CVD complications bringing up the participation of untraditional risk factors such as advanced glycation end products (AGEs), carbamoylation and changes in HDL proteome and functionality. We analyzed HDL composition, proteome, chemical modification and functionality in non-dialytic DKD subjects categorized according to estimated glomerular filtration rate (eGFR) and urinary albumin excretion rate (AER). Methods: DKD individuals were divided in eGFR>60 mL/min/1.73 m2 plus AER stages A1 and A2 (n=10) and eGFR<60 plus A3 (n=25) and matched by age with control subjects (eGFR>60; n=8). Results: Targeted proteomic analyses quantified 28 proteins associated with HDL in all groups, although only 2 were more expressed in eGFR<60+A3 group in comparison to controls: apolipoprotein D (apoD) and apoA-IV. HDL from eGFR<60+A3 presented higher levels of total AGEs (20%), pentosidine (6.3%) and carbamoylation (4.2 x) and a reduced ability in removing 14C-cholesterol from macrophages (33%) in comparison to controls. The antioxidant role of HDL (lag time for LDL oxidation) was similar among groups but HDL from eGFR<60+A3 presented a higher ability in inhibiting the secretion of IL6 and TNF alpha (95%) in LPS-elicited macrophages in comparison to control group. Conclusion: The increment in ApoD and ApoA-IV seems to counteract the HDL chemical modification by AGE and carbamoylation that contributes for HDL loss of function in well-established DKD.