Endocrine Abstracts

Neuropathic pain (NP) is a microvascular complication affecting between 30-50% of people living with diabetes. Current painkillers including non-steroidal pain killers and anti-convulsant are ineffective. At the level of the spinal cord (SC), capillary regression is associated with the onset of NP in diabetic rodent models. Our aim was to investigate angiotensin II mediated pericyte activation in relation to vascular degeneration and the onset of NP. Adult male C57Bl/6J mice were fed either a standard diet (18% kcal from fat) or high fat diet (HFD; 60% kcal from fat) for 8 weeks. HFD fed mice led to an increased blood glucose compared to standard diet (17.3%¬¬↑¬ blood glucose mmol/l, *P<0.015, n=8 per group). This was accompanied by a reduction in nociceptive withdrawal latency to thermal stimuli (41.95%↓,***P<0.0003, HFD vs. standard diet). There was increased capillary (CD31 positive) breakdown depicted by reduced vessel branching count in the lumbar SC (37.9%↓*P<0.024, n=6) and reduced angiotensin converting enzyme 2 (ACE2) expression (*P<0.05) in the HFD fed rodents. Following this the angiotensin II type 1 receptor antagonist, Losartan, was investigated as a potential analgesic agent in HFD fed rodents. At week 8, Losartan (intraperitoneal delivered, 20 mg/kg) induced increased withdrawal latency to thermal stimuli in HFD rodents compared to vehicle treated HFD fed rodents (intraperitoneal delivered, PBS) (78.4%↑¬****P<0.0001 HFD+losartan vs. HFD+vehicle). Furthermore, primary mouse SC pericytes were cultured to investigate renin-angiotensin system activity within high glucose environments. ACE2 showed reduced expression in high glucose (47 mmol/l, 29.27%↓ *P<0.035, n=5) compared to normal glucose (17 mmol/l, n=3) environments. These data demonstrate that hyperglycaemia induces an angiotensin II dependent pericyte vasoconstriction that causes microvessel degeneration in the spinal cord of high fat rodents. This initiates the breakdown of the blood-spinal cord-barrier breakdown, a mediator of diabetic neuropathic pain.