Hypertension is associated with the reduction in epidermal small fibres independently of sural nerve inflammation in type 2 diabetic subjects

• Published in: Journal of neurochemistry Vol. 169; no. 2; pp. e16235 - n/a
• Main Authors: Wang, Zhenchao, Kushibiki, Hanae, Tarusawa, Takefusa, Osonoi, Sho, Ogasawara, Saori, Miura, Chinatsu, Sasaki, Takanori, Ryuzaki, Masaki, Yagihashi, Soroku, Mizukami, Hiroki
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2025; John Wiley and Sons Inc
• Subjects: Adult; Aged; Autopsies; autopsy; Density; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - pathology; Diabetic Neuropathies - pathology; diabetic polyneuropathy; Diffusion barriers; Epidermis - innervation; Epidermis - pathology; Female; Humans; Hyperglycemia; Hypertension; Hypertension - complications; Hypertension - pathology; IENFD; Immune system; Infiltration; Inflammation; Inflammation - pathology; Inflammatory response; Macrophages; Macrophages - pathology; Male; Middle Aged; Nerve Fibers - pathology; Nerves; Original; Polyneuropathy; Sural nerve; Sural Nerve - pathology; Thickness; macrophages; diabetic polyneuropathy; IENFD; autopsy; hypertension
• DOI: 10.1111/jnc.16235
• ISSN: 0022-3042; 1471-4159

Diabetic polyneuropathy (DPN) is a multifactorial disease associated not only with hyperglycaemia but also with circulatory disturbances such as hypertension. A close interaction between the immune system and hypertension is known. It remains unclear whether the inflammatory response is associated with hypertension in the pathology of human DPN. Autopsied patients were evaluated: 7 non‐diabetic patients (nDM), 11 non‐diabetic patients with hypertension (nDMHT), 6 patients with diabetes (DM) and 9 patients with hypertension and diabetes (DMHT). Intraepidermal nerve fibre density (IENFD) was examined by immunofluorescent staining. Dissected sural nerve (SNs) were morphometrically quantified. Dermal and endoneurial macrophage infiltration was evaluated by double immunostaining using anti‐CD68 and anti‐CD206 antibodies. IENFD was significantly decreased in DM compared to nDM (p < 0.05) and was further decreased in DMHT (p < 0.05). Myelinated nerve fibre density (MNFD) in the SN was significantly decreased in DM compared with nDM (p < 0.05) and further decreased in DMHT (p < 0.01 vs. DM). The infiltration of CD206−/CD68+ proinflammatory macrophages in the SN was significantly increased in DM compared to nDM (p < 0.05), whilst the number of CD206+/CD68+ anti‐inflammatory macrophages was decreased in DM (p < 0.05). Hypertension had no impact on macrophage infiltration. The ratio of CD206− and CD206+ macrophage was negatively correlated with MNFD (r = 0.42, p < 0.05) but not IENFD (r = 0.30, p = 0.09). Dermal CD206+ macrophage infiltration was similar amongst all groups. Diabetes complicated by hypertension significantly increased the total diffusion barrier thickness (p < 0.01 vs. DM). Total diffusion barrier thickness was inversely correlated with both IENFD (r = ‐0.59, p < 0.01) and MNFD (r =‐0.62, p < 0.01). Our results suggest that vascular factors and inflammation might be synergistically involved in pathological changes in human diabetic patients through different mechanisms. In this study, the effects of hypertension and local inflammation on the human diabetic peripheral nerve were assessed. Diabetic patients complicated with hypertension showed a marked decrease in intraepidermal and sural myelinated nerve fibre density. In diabetic sural nerves, hypertension had no impact on proinflammatory macrophage infiltration, which was inversely correlated with only myelinated nerve fibre density. On the other hand, the total diffusion barrier thickness of endoneurial vessels increased in hypertension patients, which was inversely correlated with both intraepidermal and myelinated nerve fibre density. Our results suggest that hypertension can exacerbate neuropathy in human diabetic patients independently of local inflammation.