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已发表论文
色素上皮衍生因子通过降解肾脏异位脂肪沉积及抑制肾小管上皮细胞代谢重编程来缓解糖尿病肾纤维化
Received 27 May 2025
Accepted for publication 6 November 2025
Published 14 November 2025 Volume 2025:18 Pages 4211—4227
DOI https://doi.org/10.2147/DMSO.S536576
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Rebecca Baqiyyah Conway
Tuohua Mao,1 Yingying Bi,2 Yan Bao1
1Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
Correspondence: Yingying Bi, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, Email 2021203020005@whu.edu.cn Yan Bao, Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, Email baoyan@whu.edu.cn
Background: The pathogenesis of diabetic nephropathy (DKD) remains unclear; however, existing literature suggests that ectopic fat deposition and metabolic reprogramming contribute to the development of diabetic renal fibrosis. Our previous studies have demonstrated that pigment epithelium-derived factor (PEDF) can alleviate diabetic renal fibrosis.
Methods: In this study, db/db mice were utilized as animal models to simulate type 2 diabetic nephropathy, and human proximal tubular epithelial cells (HK-2) cultured under conditions of high glucose and high palmitic acid were employed for in vitro analysis to investigate the mechanism through which PEDF improves diabetic renal fibrosis.
Results: The results revealed that implanting the PEDF gene via AAV9 effectively improved renal function and blood lipid levels in db/db mice, and alleviated renal tubular injury, urinary albumin excretion, renal ectopic fat accumulation, and renal fibrosis in these mice. The protein expressions in renal peroxisomes and mitochondria could be up-regulated by PEDF, leading to enhanced β-oxidation of fatty acids in db/db mice. This effect was associated with the up-regulation of the ATGL-PPARα pathway and the down-regulation of the HIF-1α-HK2 pathway. It was observed that PEDF effectively mitigated lipid deposition and transdifferentiation of HK-2 cells by activating the ATGL-PPARα pathway, while concurrently inhibiting HIF-1α-HK2 pathway and glycolysis. Furthermore, PEDF facilitated fatty acid β-oxidation in both mitochondria and peroxisomes of HK-2 cells through the ATGL-PPARα pathway.
Conclusion: PEDF can reduce abnormal renal fat accumulation and regulate metabolic reprogramming of renal tubular epithelial cells, thereby alleviating diabetic renal fibrosis.
Keywords: PEDF, diabetic renal fibrosis, kidney ectopic fat deposition, metabolic reprogramming
1Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
Correspondence: Yingying Bi, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, Email 2021203020005@whu.edu.cn Yan Bao, Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, Email baoyan@whu.edu.cn
Background: The pathogenesis of diabetic nephropathy (DKD) remains unclear; however, existing literature suggests that ectopic fat deposition and metabolic reprogramming contribute to the development of diabetic renal fibrosis. Our previous studies have demonstrated that pigment epithelium-derived factor (PEDF) can alleviate diabetic renal fibrosis.
Methods: In this study, db/db mice were utilized as animal models to simulate type 2 diabetic nephropathy, and human proximal tubular epithelial cells (HK-2) cultured under conditions of high glucose and high palmitic acid were employed for in vitro analysis to investigate the mechanism through which PEDF improves diabetic renal fibrosis.
Results: The results revealed that implanting the PEDF gene via AAV9 effectively improved renal function and blood lipid levels in db/db mice, and alleviated renal tubular injury, urinary albumin excretion, renal ectopic fat accumulation, and renal fibrosis in these mice. The protein expressions in renal peroxisomes and mitochondria could be up-regulated by PEDF, leading to enhanced β-oxidation of fatty acids in db/db mice. This effect was associated with the up-regulation of the ATGL-PPARα pathway and the down-regulation of the HIF-1α-HK2 pathway. It was observed that PEDF effectively mitigated lipid deposition and transdifferentiation of HK-2 cells by activating the ATGL-PPARα pathway, while concurrently inhibiting HIF-1α-HK2 pathway and glycolysis. Furthermore, PEDF facilitated fatty acid β-oxidation in both mitochondria and peroxisomes of HK-2 cells through the ATGL-PPARα pathway.
Conclusion: PEDF can reduce abnormal renal fat accumulation and regulate metabolic reprogramming of renal tubular epithelial cells, thereby alleviating diabetic renal fibrosis.
Keywords: PEDF, diabetic renal fibrosis, kidney ectopic fat deposition, metabolic reprogramming