Abstract
Collagen type VI (COL6) deposition occurs in various glomerular diseases, causing serious pathological damage like nodular lesions. However, the mechanisms underlying the deposition of COL6 remain unclear. In renal biopsy samples, immunohistochemical analyses revealed that COL6 and phosphorylated histone H2AX (γ-H2AX), a DNA damage marker, were detected mainly in diabetic nodular glomerulosclerosis, in which the γ-H2AX-positive area was identified as the independent factor significantly associated with the COL6-positive area (β: 0.539, t = 2.668). In in vitro studies, COL6 secretion from human renal glomerular endothelial cells (HRGECs) was assessed by measuring the decrease in the cytoplasmic COL6-positive cells and an increase in the amount of COL6 in the culture medium. Mitomycin C (MMc) treatment of HRGECs increased the number of γ-H2AX-positive cells and COL6 secretion, which were suppressed by a specific inhibitor of ataxia telangiectasia and Rad3-related (ATR). MMc-induced COL6 secretion was also suppressed by Annexin A2 (ANXA2) siRNA transfection. Moreover, the inhibition of ATR activity did not induce any extra suppression in the MMc-induced COL6 secretion by ANXA2 siRNA transfected cells. These results confirm that nodular glomerulosclerosis partially results from DNA damage in the glomerulus and that DNA damage-induced COL6 secretion from HRGECs occurs through an ATR and ANXA2-mediated pathway.
Highlights
Nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) is one of the typical glomerular lesions in diabetic nephropathy
We examined this correlation in various kidney diseases, especially focusing on those with nodular glomerulosclerosis
We found that DNA damage in the glomerulus is positively correlated with COL6 deposition and the formation of nodular glomerulosclerosis in various kidney diseases
Summary
Nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) is one of the typical glomerular lesions in diabetic nephropathy. Nodular glomerulosclerosis is not specific for diabetic nephropathy; it is detected in many other kidney diseases derived from a number of causes, including smoking, obesity, and hypertension[2]. Further studies that elucidate the mechanisms contributing to the deposition of COL6 in nodular glomerulosclerosis will be valuable for discovering new therapeutic targets for kidney disease. We previously demonstrated that DNA damage in the glomerular endothelial cells and COL6 deposition in the glomeruli are positively correlated in patients with renal g rafts[7]. Both renal allografting and diabetic nephropathy induce DNA damage in glomerular endothelial cells[8,9]. A recently performed study has revealed that ANXA2 participates in the secretion of COL6 by bronchial epithelial c ells[18]
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