Abstract
We previously reported a critical role of reticulon (RTN) 1A in mediating endoplasmic reticulum (ER) stress in kidney tubular cells and the expression of RTN1A correlates with the renal function and the severity of kidney injury in patients with diabetic nephropathy (DN). Here, we determined the roles of RTN1A and ER stress in podocyte injury and DN. We used db/db mice with early unilateral nephrectomy (Unx) as a murine model of progressive DN and treated mice with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress. We found increased expression of RTN1A and ER stress markers in the kidney of db/db-Unx mice. Treatment of TUDCA not only attenuated proteinuria and kidney histological changes, but also ameliorated podocyte and glomeruli injury in diabetic mice, which were associated with reduction of RTN1A and ER stress marker expression in the podocytes of TUDCA-treated mice. In vitro, we showed RTN1A mediates albumin-induced ER stress and apoptosis in human podocytes. A positive feedback loop between RTN1A and CHOP was found leading to an enhanced ER stress in podocytes. Our data suggest that ER stress plays a major role in podocyte injury in DN and RTN1A might be a key regulator of ER stress in podocytes.
Highlights
Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN5–7
All db/db mice had increased body weight and blood glucose levels compared with db/m mice at 16 weeks of age. db/db mice that underwent Unx had increased serum creatinine level, increased urine albumin/creatinine ratio (UACR), and more severe kidney histological changes at 16 weeks of age compared with age matched db/db-sham mice as well as db/db-sham mice at 20 weeks of age (Supplementary Table 1, Supplementary Fig. 1)
Reduction of podocyte number due to apoptosis and detachment correlates with the amount of proteinuria and rate of progression in DN21
Summary
Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN5–7. Elevated urinary protein excretion in humans is known to be associated with tubular injury and ER stress[8, 10, 11]. Several studies suggest an association of ER stress with podocyte injury[6, 15]. In the previous study[16], we identified a critical role of endoplasmic reticulum (ER)-associated protein reticulon-1A (RTN1A) in regulation of ER stress in kidney tubular cells. In the current study, we examined whether inhibition of ER stress by Tauroursodeoxycholic acid (TUDCA), a well-known ER stress inhibitor, attenuated podocyte injury and diabetic kidney disease through regulation of RTN1A and ER stress markers in a murine model of progressive DN. We examined the role RTN1A in regulation of albumin-induced ER stress in cultured podocytes. Our studies provide us a better understanding of ER stress in inducing podocyte injury in DN
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