Humanin prevents intra-renal microvascular remodeling and inflammation in hypercholesterolemic ApoE deficient mice

Aims: Humanin (HN) is an endogenous mitochondrial-derived cytoprotective peptide that has shown protective effects against atherosclerosis and is expressed in human vessels. However, its effects on the progression of kidney disease are unknown. We hypothesized that HN would protect the kidney in the early phase of atherogenesis. Main methods: Forty-eight mice were studied in four groups (n = 12 each). Twenty-four ApoE deficient mice were fed a 16-week high-cholesterol diet supplemented with saline or HN (4 mg/kg/day, intraperitoneal). C57BL/6 mice were fed a normal diet supplemented with saline or HN. Microvascular architecture was assessed with micro-CT and vascular wall remodeling by alpha-SMA staining. The effects of HN on angiogenesis, inflammation, apoptosis and fibrosis were evaluated in the kidney tissue by Western blotting and histology. Key findings: Cortical microvascular spatial density and media/lumen area ratio were significantly increased in high-cholesterol diet fed ApoE deficient mice, but restored by HN. HN up-regulated the renal expressions of anti-angiogenic proteins angiostatin and TSP-1, and inhibited angiopoietin-1. HN attenuated inflammation by down-regulating MCP-1, TNF-alpha and osteopontin. HN also tended to restore pSTAT3 and attenuated Bax expression, suggesting blunted apoptosis. Kidney collagen IV expression was alleviated by HN treatment. Significance: HN attenuates renal microvascular remodeling, inflammation and apoptosis in the early stage of kidney disease in hypercholesterolemic ApoE ^-/- mice. HN may serve as a novel therapeutic target to mitigate kidney damage in early atherosclerosis.