Upregulation of Piezo2 and increased extracellular matrix protein in diabetic kidney disease mice

Mechanical forces such as glomerular hyperfiltration are crucial in the pathogenesis and progression of diabetic kidney disease. Piezo2 is a mechanosensitive cation channel and plays a major role in various biological and pathophysiological phenomena. We previously reported Piezo2 expression in mouse and rat kidneys and its alteration by dehydration and hypertension. To elucidate the alteration of Piezo2 expression and its consequences in a mouse model of diabetic kidney disease, we used high salt-fed male KK-A^y mice, an accelerated genetic model of diabetic kidney disease. KK-A^y mice exhibited marked obesity, hyperglycemia, elevated blood pressure, higher creatinine clearance, and overt albuminuria. Histopathological analysis revealed glomerular hypertrophy, mesangial expansion, macrophage infiltration, tubular vacuolization, and interstitial fibrosis. The mRNA and protein expression analyses revealed (1) increased fibronectin protein expression in the glomerular areas, (2) upregulated Piezo2 expression in the glomerular mesangial cells and interstitial region, (3) increased Piezo2 and the fibronectin-coding gene Fn1 mRNA, and (4) a strong correlation of Piezo2 expression with that of Fn1 in the kidneys of diabetic kidney disease mice. Piezo2 upregulation and fibronectin accumulation were alleviated by an angiotensin II receptor blocker. In accordance with these in vivo results, in vitro study demonstrated that Piezo2 overexpression increased fibronectin production in HEK293T cells. In conclusion, we demonstrated that Piezo2 expression was upregulated in glomerular mesangial cells in a mouse model of diabetic kidney disease. Our results suggest that Piezo2 contributes to the progression of diabetic kidney disease by mediating glomerular fibronectin production, leading to glomerulosclerosis. Hyperfiltration is crucial in the pathogenesis of diabetic kidney disease. We showed that Piezo2 expression is upregulated in mesangial cells of diabetic kidney disease mice with glomerular fibronectin accumulation. Piezo2 overexpression increased fibronectin production in HEK293T cells. Piezo2 may contribute to diabetic kidney disease progression by mediating glomerular fibronectin production.