The role of α2-adrenoceptors in podocyte damage caused by puromycin aminonucleoside-induced nephrotic syndrome in rats

Nephrotic syndrome, characterised by proteinuria and hypoalbuminaemia, is caused by the dysregulation of glomerular podocytes and is a significant contributor to chronic kidney disease (CKD). Sympathetic neurotransmitter noradrenaline, acting through adrenoceptor signalling, contributes to progression of various diseases, including CKD. We previously reported that treatment with yohimbine, an α2-adrenoceptor antagonist, decreased urinary protein excretion in 5/6 nephrectomy-induced CKD rat model and that α2-adrenoceptors are localised in podocytes. This suggested that noradrenaline may induce proteinuria via α2-adrenoceptors in podocytes. Therefore, this study investigated the renoprotective effects of yohimbine in puromycin aminonucleoside (PAN)-induced nephrotic syndrome. Male Sprague-Dawley rats were randomly allocated to sham-operated, PAN (50 mg/kg, i.v.), and PAN + yohimbine (3 mg/L in drinking water) groups. PAN group exhibited increased urinary protein, decreased plasma protein, and increased urinary and plasma noradrenaline levels compared to sham group. Furthermore, pronounced infiltration of CD68-positive cells was observed in the PAN group. The expression levels of the podocyte markers podocin and nephrin were lower in PAN rats than in control rats. Conversely, podocytes in PAN rats exhibited increased desmin, transforming growth factor (TGF)-β1, and cleaved caspase 3 expressions along with higher prevalence of apoptotic cells. Treatment with yohimbine reduced proteinuria and hypoalbuminemia, along with suppressing the downregulation of podocin expression. Furthermore, yohimbine suppressed the expression of desmin, TGF-β1, cleaved caspase-3, and apoptotic cells in glomeruli. Administration of yohimbine reduced the infiltration of CD68-positive cells in the kidney tissue. Collectively, these findings suggest that noradrenaline may promote podocyte injury in PAN-induced nephrotic syndrome via α2-adrenoceptors.