Abstract
Objective The generation of hyperglycemia-induced reactive oxygen species (ROS) is a key event in diabetic nephropathy (DN) development. Since forkhead box class O1 (FOXO1) is associated with oxidative stress and shows a positive effect on DN, its role on renal function and the underlying mechanism is still unclear. Methods We examined the role of FOXO1 in vivo (in a transgenic diabetic mouse model overexpressing Foxo1) and in vitro (in human HK-2 cells with FOXO1 knockin (KI) and knockout (KO) cultured under high glucose). Results Renal proximal tubular cells of kidney biopsies from patients with DN showed tubulointerstitial fibrosis and apoptosis. Accordingly, these proximal tubular injuries were accompanied by the increase of ROS generation in diabetic mice. Tissue-specific Foxo1 overexpression in transgenic mice had a protective effect on the renal function and partially reversed tubular injuries by attenuating the diabetes-induced increase in TXNIP and decrease in the TRX levels. FOXO1 knockin and knockout HK-2 cells were constructed to identify the associations between FoxO1 and TXNIP-TRX using CRISPR/CAS9. Similarly, the effects of FOXO1 KI and KO under high glucose were significantly modulated by the treatment of TRX inhibitor PX-12 and TXNIP small interfering RNA. In addition, TXNIP and TXN were identified as the direct FOXO1 transcriptional targets by chromatin immunoprecipitation. Conclusion The regulatory role of FOXO1/TXNIP-TRX activation in DN can protect against the high glucose-induced renal proximal tubular cell injury by attenuating cellular ROS production. Modulating the FOXO1/TXNIP-TRX pathway may be a new therapeutic target in DN.
Highlights
Reactive oxygen species (ROS) are increasingly recognized as the most important factors regulating altered metabolic pathways in differentiated cells, ultimate contributing to inflammation, fibrosis, dysfunction, and apoptosis [1, 2]
Given that ROS generation in renal proximal tubular cells (RPTCs) is increased under diabetic conditions [6], ROS accumulation might accelerate the irreparable progression of diabetic nephropathy (DN)
We further investigated whether Foxo1 overexpression could attenuate the protein indicators of apoptosis and interstitial fibrosis induced by hyperglycemia in mouse RPTCs
Summary
Reactive oxygen species (ROS) are increasingly recognized as the most important factors regulating altered metabolic pathways in differentiated cells, ultimate contributing to inflammation, fibrosis, dysfunction, and apoptosis [1, 2]. Diabetic nephropathy (DN) is an important cause of end-stage renal disease [3], and accumulating evidence implicates renal proximal tubular cells (RPTCs) as drivers of the structural and functional changes in diabetic kidneys [4, 5]. Thioredoxin-interacting protein (TXNIP) is a negative regulator of thioredoxin (TRX). TXNIP-TRX appear to be important contributors among the enzymatic systems implicated in ROS generation and renal oxidative stress [7]. ROS plays a critical role in stimulating the growth factors and cytokines like transforming growth factor-beta 1 and connective tissue growth factor [9]. These ROS-induced profibrotic factors lead to an excessive buildup of extracellular matrix, which further exacerbates kidney injury [10]
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