A negative feedback loop of H19/miR-675/EGR1 is involved in diabetic nephropathy by downregulating the expression of the vitamin D receptor.
J Cell Physiol. 2019 Feb 27. doi: 10.1002/jcp.28373.
Fan W1,2, Peng Y3, Liang Z4, Yang Y5, Zhang J1.
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- Type 1 Diabetes association with poor Vitamin D Receptor: 39 studies – April 2017
- Type 1 diabetes 1.6 times more likely if a Vitamin D Receptor problem – Feb 2017
- Diabetic Retinopathy 2 X more likely if poor Vitamin D Receptor – meta-analysis Nov 2016
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- Vitamin D activates the hypothalamus (in rodents) to reduce weight and diabetes– May 2016
- Diabetes (T2) 16 percent more likely if Vitamin D receptor problem – Oct 2015
- Type 1 diabetes associated with faulty Vitamin D receptor genes – May 2013
- Vitamin D receptor gene associated with 50 percent more type 2 Diabetes – meta-analyses 2013, 2016
We aimed to explore the regulatory relationship among the long noncoding RNA H19, micorRNA-675 (miR-675), the vitamin D (VD) receptor (VDR), and the early growth response protein 1 (EGR1) in the pathogenesis of diabetic nephropathy (DN) among patients with diabetes mellitus (DM).
Expression levels of H19, miR-675, VDR, and EGR in patients or CIHP-1/HEK 293 cells were measured via quantitative reverse-transcription polymerase chain reaction and western blot analysis. Computational analysis and luciferase assays were performed to determine EGR1 as a target gene of miR-675.
The relative expression of miR-675 was higher in the presence of H19, whereas the expression of both VDR and EGR1 messenger RNA was decreased in the presence of H19 or miR-675. However, relative expression of H19 and miR-675 was increased, whereas VDR expression was suppressed upon the treatment of 1,25-dihydroxyvitamin D3 or EGR1. VDR was identified as a target gene of miR-675. The H19 promoter and EGR1 increased the luciferase activity of cells transfected with wild-type VDR. Compared with DM patients free of DN, the levels of H19 and miR-675 were increased in the DN(+) group, whereas the levels of VDR and EGR1 were decreased.
In summary, the above results indicate the presence of a negative feedback loop in the pathological mechanism of DN, where H19 downregulates the expression of VDR by upregulating the expression of miR-675, whereas reduced VDR expression subsequently reduced the expression of EGR1. Moreover, reduced EGR1 expression inhibits H19 expression, thus forming a negative feedback loop required to maintain the homeostasis of VDR and to reduce the incidence of DN.