ABSTRACT
BACKGROUND: Homozygous familial hypercholesterolemia (hoFH) is a rare genetic disorder leading to extremely increased LDL-cholesterol (LDL-C), resulting in high cardiovascular risk in early childhood. Lipid apheresis (LA) is an effective treatment and should be started as early as possible to prevent premature cardiovascular events. As peripheral punctures in children can be challenging due to small vessels and anxiety, this study aimed to evaluate feasibility and safety of central venous catheters (CVCs) as vascular access for LA in young children with hoFH. METHODS: Retrospective analysis (2016-2019) on four children with hoFH aged 3-5 years, performing weekly or biweekly LA with a CVC. RESULTS: LDL-C decreased by> 60%. In three children, the use of a permanent CVC for 698, 595, and 411 days, respectively, avoided difficult peripheral access, without the occurrence of occlusion or thrombosis. Unfortunately, one child had recurrent CVC-related infections and needed an arteriovenous fistula from the age of 5. Although the mean dwell time per catheter was 212 days, there were, as expected, severe side effects of early catheter infections with sepsis and accidental self-removal. Starting LA at an early age improved or stabilized carotid intima-media thickness (IMT) in three children. However, IMT did increase in one child caused by intolerance to peripheral punctures and LA interruption. CONCLUSIONS: Permanent CVCs are a viable temporary access choice for LA in young children with hoFH until peripheral venipuncture is practicable. The risk of CVC-related infections needs to be taken into account.
Subject(s)
Blood Component Removal , Homozygous Familial Hypercholesterolemia , Hyperlipoproteinemia Type II , Blood Component Removal/methods , Carotid Intima-Media Thickness , Child, Preschool , Cholesterol, LDL , Homozygote , Humans , Hyperlipoproteinemia Type II/genetics , Hyperlipoproteinemia Type II/therapy , Retrospective StudiesABSTRACT
Increased O-linked ß-N-acetylglucosamine glycosylation (O-GlcNAcylation) is a known contributor to diabetes; however, its relevance in diabetic nephropathy (DN) is poorly elucidated. Here, we studied the process and enzymes of O-GlcNAcylation with a special emphasis on Akt-endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP)72 signaling. Since tubular injury is the prominent site of DN, the effect of hyperglycemia was first measured in proximal tubular (HK2) cells cultured in high glucose. In vivo O-GlcNAcylation and protein levels of O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), phosphorylated (p)Akt/Akt, peNOS/eNOS, and HSP72 were assessed in the kidney cortex of streptozotocin-induced diabetic rats. The effects of various renin-angiotensin-aldosterone system (RAAS) inhibitors were also evaluated. In proximal tubular cells, hyperglycemia-induced OGT expression led to increased O-GlcNAcylation, which was followed by a compensatory increase of OGA. In parallel, peNOS and pAkt levels decreased, whereas HSP72 increased. In diabetic rats, elevated O-GlcNAcylation was accompanied by decreased OGT and OGA. RAAS inhibitors ameliorated diabetes-induced kidney damage and prevented the elevation of O-GlcNAcylation and the decrement of pAkt, peNOS, and HSP72. In conclusion, hyperglycemia-induced elevation of O-GlcNAcylation contributes to the progression of DN via inhibition of Akt/eNOS phosphorylation and HSP72 induction. RAAS blockers successfully inhibit this process, suggesting a novel pathomechanism of their renoprotective action in the treatment of DN.
Subject(s)
Acetylglucosamine/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/metabolism , Kidney/metabolism , Signal Transduction/physiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Cell Line , Cell Survival/drug effects , Enalapril/pharmacology , Glycosylation , HSP72 Heat-Shock Proteins/metabolism , Humans , Kidney/drug effects , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Losartan/pharmacology , Male , Nitric Oxide Synthase Type III/metabolism , Phosphorylation/drug effects , Protein Processing, Post-Translational/drug effects , Protein Processing, Post-Translational/physiology , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Renin-Angiotensin System/drug effects , Signal Transduction/drug effectsABSTRACT
Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers.
