No abstract

Diabetic nephropathy (DN) is a serious complication of longstanding diabetes affecting up to 30% of all diabetes patients and is the main cause of end-stage kidney disease globally. Current standard treatment e.g. ACE-inhibitors like enalapril merely offers a delay in the progression leading to DN. Herein, we describe in two preclinical models evidence to local effects on the inflammatory signatures after intervention treatment with enalapril which provides enhanced understanding of the mechanism of ACE inhibitors. Enalapril transiently reduced albuminuria in both the db/db and the STZ-induced DN models with established disease, without modulating the HbA1c%. Albuminuria was strongly associated with loss of leukocytes, particularly B cells, but also of sub-populations of macrophages and CD4(+) T cells. The remaining kidney macrophages were polarized into a M2-like sub-population with reduced surface expression of the M1-like macrophage marker CD11c and enhanced expression of galectin-3. Enalapril treatment counteracted the reduction of leukocytes in the diabetic kidney towards levels noted in the non-diabetic kidney. Particularly, a subset of macrophages was increased and a clear expansion of CD4(+) and CD8(+) T cells was observed. However, enalapril failed to modulate the B cell compartment. Interestingly, enalapril treatment resulted in a re-polarization of the macrophages towards a M1-like phenotype characterized by elevated levels of CD11c with moderate down-regulation of the M2 marker galectin-3. The data demonstrate that ACE inhibition in pre-clinical models of DN shows a transient beneficial effect on albuminuria which is unexpectedly associated with restoration of T cells and M1-like macrophages in the kidney.

Marine n-3 long-chain PUFA (n-3 LCPUFA) may have a beneficial effect on several aspects of the metabolic syndrome (dyslipidaemia, insulin resistance, hypertension and abdominal obesity). The metabolic syndrome is increasing in prevalence during adolescence, but only few studies have investigated the effects of n-3 LCPUFA in adolescence. The present study examines associations between fish intake (assessed by a 7 d pre-coded food diary), erythrocyte (RBC) DHA status (analysed by GC) and metabolic syndrome measures (anthropometry, blood pressure and plasma lipids, insulin and glucose) in 109 17-year-old children from the Copenhagen Birth Cohort Study. Of the children, 8 % were overweight or obese and few showed signs of the metabolic syndrome, but all the metabolic syndrome variables were correlated. Median fish intake was 10·7 (interquartile range 3·6-21·2) g/d. Boys tended to have a higher fish intake (P¼ 0·052), but girls had significantly higher RBC levels of DHA (P¼ 0·001). Sex and fish intake explained 37 % of the variance in RBC-DHA (P,0·001). After adjusting for confounders, high DHA status was found to be significantly correlated with higher systolic blood pressure (P¼ 0·014) and increased fasting insulin (P¼ 0·018), but no adverse association was observed with the mean metabolic syndrome z-score. Overall, the present study showed the expected association between fish intake and RBC-DHA, which in contrast to our expectations tended to be associated with a poorer metabolic profile. Whether these results reflect the physiological function of n-3 LCPUFA, lifestyle factors associated with fish intake in Denmark, or mere chance remains to be investigated.

Secretory sphingomyelinase (sSMase) has been suggested to be involved in the development of cardiovascular diseases as well as other human pathologies. To deduce whether dietary fatty acid composition affects the circulating activity of this enzyme, we have compared its activity in serum from rats that had been given a diet containing either butter or a highly n‐6 polyunsaturated [grapeseed oil (GSO)] fat source for 14 wk. The results show that intake of GSO increases the activity of this ceramide‐producing enzyme by about 45%, when compared with intake of butter (387 ± 16 pmol/mL·h vs. 266 ± 15 pmol/mL·h; p <0.001). Furthermore, there was a strong negative correlation between sSMase activity and n‐3 PUFA concentration in serum (p <0.001). Despite the substantial increase in activity, there was no difference in either the circulating substrate (sphingomyelin) or product (ceramide) in the serum. However, since the sSMase activity in the endothelial wall has been implicated to be involved in both atherogenesis and thrombosis, these findings are of interest in the interpretation of dietary fatty acid effects on cardiovascular health.