MO630SNOGO-B IS AN IMPORTANT CONTRIBUTOR TO GLOMERULAR ENDOTHELIAL CELL STABILITY AND VASCULAR REMODELLING INTERVENING ON VEGFA/VEGFR2 SIGNALLING

Background and Aims Nogo-B is an endoplasmic reticulum protein present as a full length and circulating soluble isoform (sNogo-B) corresponding to the first ∼200aa of the N-terminus. Nogo-B is expressed in glomerular endothelial cells (GECs) and is downregulated in the diabetic glomeruli; its repletion, ameliorates diabetic glomerulopathy. However, the precise biological role of Nogo-B and its soluble form in GEC is not well understood. We hypothesise that sNogo-B could modulate VEGFA/VEGFR2 signalling, and vascular remodelling resulting in improved GECs health and vascular remodelling (vessel repair/new vessel formation). We predict that this effect may be mediated by changes in VEGFA/VEGFR2 signalling; a critical signalling pathway which regulates blood vessel function in physiology and disease. Method For this experiment we used human conditionally immortalised GECs. Cells were used after differentiation at 37°. GECs were infected with adenovirus vector expressing sNogo-B or identical vector lacking sNogo-B cDNA (control vector). Cells were serum starved (4 hours, FBS 2%) and exposed to VEGFA (50 ng/ml) for 5’ 10’ 15’ min and VEGFR2 phosphorylation assessed with western immunoblotting. Results VEGFA-Mediated VEGFR2 phosphorylation was upregulated in wild-type GECs after 15 min VEGFA incubation (P<0.05) n=4. sNogo-B overexpression upregulated the sNogo-B protein level in the supernatant by 10 fold and prevented VEGFA/VEGFR2 phosphorylation in human immortalized glomerular endothelial cells(P<0.05). Conclusion sNogo-B prevents the VEGFA mediated VEGFR2 phosphorylation in GECs. Upregulation of VEGFA/VEGFR2 signalling has been implicated in diabetic glomerulopathy. sNogo-B inhibition of VEGFA/VEGFR2 signalling opens new investigations looking at the potential role of sNogo-B as therapeutic target in diabetic nephropathy.

Characteristic Renal Histology of a 81-Year-Old Patient with a 30-Year History of Diabetes Mellitus: A Case Report

A renal histology of an 81-year-old man with a 30-year history of diabetes mellitus (DM), as well as diabetic retinopathy and neuropathy, was examined. The patient’s blood pressure was controlled within the normal range (less than 140/75 mmHg) using antihypertensive agents including angiotensin receptor blocker. Edematous management was achieved by a strict salt diet (less than 6 g/per day). However, this patient’s glycemic control was poor with HbA1c 8–10%. Serum creatinine was 0.87 mg/dL and estimated globular filtration rate (eGFR) was 64 ml/min/1.73m2. Urinary protein excretion was 1.5 g/day. This patient’s renal biopsy showed linear staining for IgG along the GBM by immunofluorescence microscopy, but light microscopy showed almost intact glomeruli, and the GBM was not thickened as revealed by electron microscopy with a width of 288–368 nm (< 430 nm). While arteriolar hyalinosis was severe, and polar vasculosis was observed around the glomerular vascular pole. This case indicates that long-standing hyperglycemia may induce polar vasculosis by the mechanism of angiogenesis, but diabetic glomerulopathy can become minor change, only when hypertension and edematous management could be controlled strictly.