Zhongai Gao1, Ziyan Wang1, Hong Zhu2, Xinxin Yuan1, Mengdi Sun1, Jingyu Wang1, Minxia Zuo1, Xiao Cui1, Ying Han3, Yi Zhang1, Shaohua Yang1, Yongzhang Qin1, Jie Xu1, Juhong Yang4, Baocheng Chang4. 1. NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China. 2. Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China. 3. Department of Endocrinology, Tianjin Haibin People's Hospital, Tianjin, China. 4. NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China.
Abstract
BACKGROUND: Increasing evidence indicates that impaired glucose tolerance (IGT) is independently associated with chronic kidney disease, but the characteristics and underlying mechanisms remain largely unknown. METHODS: Here, the cross-sectional study was performed to study the characteristics of IGT-induced renal injury (IGT-RI). Furthermore, urine microRNA profile was evaluated and microRNAs involved in tubular injury were determined by in-vitro experiments. RESULTS: It was found that 12.1% of IGT patients had microalbuminuria, which we termed "IGT-RI." Overall, 100% of patients with IGT-RI exhibited reabsorption dysfunction and 58.3% had structural damage in the renal tubules. Two-hour postprandial insulin, retinol-binding protein, and N-acetyl-β-glucosaminidase were significantly associated with microalbuminuria and they were independent risk factors for IGT-RI. The expression of mir-7977 was altered in IGT-RI patients and may be involved in cellular response to oxidative stress. In proximal tubule epithelial cells in vitro, a high level of insulin increased the expression of mir-7977 and decreased that of sirtuin 3 (SIRT3), leading to oxidative stress. Overexpression of mir-7977 further decreased SIRT3 expression, whereas inhibition of mir-7977 had the opposite effect. Furthermore, mir-7977 can bind to the 3'-untranslated region of SIRT3 mRNA and inhibit its expression. Moreover, inhibition of SIRT3 reduced the expression of cubilin and the endocytosis of albumin. CONCLUSIONS: In conclusion, IGT-RI mainly manifests as tubular injury, especially reabsorption dysfunction. Compensatory hyperinsulinemia may be involved. A high level of insulin can activate mir-7977/SIRT3 signaling, resulting in tubular injury by inducing oxidative stress as well as reabsorption dysfunction by inhibiting the expression of cubilin, ultimately contributing to IGT-RI.
BACKGROUND: Increasing evidence indicates that impaired glucose tolerance (IGT) is independently associated with chronic kidney disease, but the characteristics and underlying mechanisms remain largely unknown. METHODS: Here, the cross-sectional study was performed to study the characteristics of IGT-induced renal injury (IGT-RI). Furthermore, urine microRNA profile was evaluated and microRNAs involved in tubular injury were determined by in-vitro experiments. RESULTS: It was found that 12.1% of IGT patients had microalbuminuria, which we termed "IGT-RI." Overall, 100% of patients with IGT-RI exhibited reabsorption dysfunction and 58.3% had structural damage in the renal tubules. Two-hour postprandial insulin, retinol-binding protein, and N-acetyl-β-glucosaminidase were significantly associated with microalbuminuria and they were independent risk factors for IGT-RI. The expression of mir-7977 was altered in IGT-RI patients and may be involved in cellular response to oxidative stress. In proximal tubule epithelial cells in vitro, a high level of insulin increased the expression of mir-7977 and decreased that of sirtuin 3 (SIRT3), leading to oxidative stress. Overexpression of mir-7977 further decreased SIRT3 expression, whereas inhibition of mir-7977 had the opposite effect. Furthermore, mir-7977 can bind to the 3'-untranslated region of SIRT3 mRNA and inhibit its expression. Moreover, inhibition of SIRT3 reduced the expression of cubilin and the endocytosis of albumin. CONCLUSIONS: In conclusion, IGT-RI mainly manifests as tubular injury, especially reabsorption dysfunction. Compensatory hyperinsulinemia may be involved. A high level of insulin can activate mir-7977/SIRT3 signaling, resulting in tubular injury by inducing oxidative stress as well as reabsorption dysfunction by inhibiting the expression of cubilin, ultimately contributing to IGT-RI.
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