Abstract
Diabetic kidney disease (DKD) is one of the most serious complications of diabetic patients. Advanced glycation end products (AGEs) induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (HK-2), resulting in renal tubulointerstitial fibrosis. However, the underlying epigenetic mechanisms remain to be further investigated. In this work, we investigated the functional role of JMJD1A involved in DKD progression. The molecular mechanism study was performed in AGEs-induced HK-2 cells by gene expression analysis, RNA sequencing (RNA-seq), and JMJD1A lentiviral knockdown and overexpression particle transfection. The results showed that AGEs could upregulate JMJD1A, and the expressions of related fibrotic factor were also increased. At the same time, in the DKD animal model induced by unilateral nephrectomy plus streptozotocin (STZ), IHC immunohistochemical staining showed that compared with the control group, the expressions of JMJD1A, FN, and COL1 in the model group were all increased, masson staining results also show that the model group has typical fibrotic changes. This is consistent with the results of our in vitro experiments. In order to determine the downstream pathway, we screened out JMJD1A downstream transcription factors by RNA-seq. Further analysis showed that JMJD1A overexpression could accelerate the progression of AGEs-induced renal fibrosis by reducing the expression of NR4A1 in HK-2 cells. Meanwhile, NR4A1 inhibitor can promote the expression of fibrosis-related factors such as VIM, a-SMA in HK-2 cells, and aggravate the process of fibrosis. Taken together, JMJD1A/NR4A1 signaling can regulate the procession of renal tubular epithelial interstitial fibrosis induced by AGEs in HK-2.
Highlights
Diabetes is a metabolic disease characterized by hyperglycemia, mainly divided into type 1 diabetes, type 2 diabetes, gestational diabetes, and special type diabetes [1, 2]
Stimulation of HK-2 cells with 400 μg/ml Advanced glycation end products (AGEs) of 12, 24, 48, and 72 h clearly resulted in relatedfibrosis proteins along with apoptosis proteins, which increased at 72 h significantly (Figures 2D,E)
NR4A1 deficient rats [tawny hypertensive rats (FHH)] developed under the genetic background of being susceptible to renal injury showed that compared with the FHH control group, the severity of renal tubular atrophy, renal tubule morphology, and interstitial fibrosis were significantly increased, accompanied by a significant increase in macrophage infiltration and upregulation of inflammatory pathway [33]. We found that both JMJD1A and NR4A1 were upregulated under the stimulation of AGEs alone, which may be due to the temporary upregulation of NR4A1 expression induced by the related fibrosis factor TGF-β, resulting in a negative feedback loop, which is consistent with previous studies [47]
Summary
Diabetes is a metabolic disease characterized by hyperglycemia, mainly divided into type 1 diabetes, type 2 diabetes, gestational diabetes, and special type diabetes [1, 2]. Diabetic kidney disease (DKD), known as diabetic glomerulosclerosis, is one of the most common microvascular complications of diabetes mellitus (DM) [3, 4]. It is the most common and serious chronic complication of type 2 diabetes mellitus (T2DM), which often leads to end-stage renal failure in patients with diabetes [5, 6]. AGEs cause oxidative stress, trigger excessive reactive oxygen species, promote the production and release of inflammatory cytokines, and aggravate the development of diabetes, chronic renal failure, cardiovascular diseases, and neurological diseases [9–12]. AGEs are the main cause of diabetic microvascular disease [13]. The continuous stimulation of risk factors usually causes damage to HK-2 cells in renal tubular epithelial cells, including high glucose levels, proteinuria, and age-modifying proteins that all lead to extracellular matrix (ECM) deposition and abnormal synthesis and degradation of epithelial proteins, leading to epithelial-mesenchymal transition (EMT) and even interstitial fibrosis [14–17]
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