Recombinant Cellular Repressor of E1A-Stimulated Genes Protects against Renal Fibrosis in Dahl Salt-Sensitive Rats

Abstract

Background: Human cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein that attenuates angiotensin II-induced hypertension, alleviates myocardial fibrosis, and improves heart function. However, the role of CREG in high-salt (HS) diet-induced hypertensive nephropathy is unclear. Methods: To determine the effects and molecular mechanisms of CREG in HS diet-induced hypertensive nephropathy, we established a hypertensive nephropathy animal model in Dahl salt-sensitive (SS) rats fed a HS diet (8% NaCl, n = 20) for 8 weeks. At week 4 of HS loading, these rats were administered recombinant CREG (reCREG; 35 µg/kg·day, n = 5) and saline (n = 5) via subcutaneously implanted pumps and were also administered the vasodilator hydralazine (20 mg/kg·day, n = 5) in drinking water. We used hematoxylin and eosin staining, Masson's trichrome staining, immunohistochemical labeling, western blotting, RT-PCR, and Tunel staining to determine the signaling pathways of CREG in HS diet-induced hypertensive nephropathy. Results: After 8 weeks of HS intake, the Dahl SS rats developed renal dys-function and severe renal fibrosis associated with reductions of 78 and 67% in CREG expression, respectively, at both mRNA and protein levels in the kidney. Administration of reC-REG improved renal function and relieved renal fibrosis. Administration of CREG also inhibited monocyte infiltration and reduced apoptosis in the kidney cells. CREG overexpression upregulated forkhead box P1 expression and inhibited the transforming growth factor-β1 signaling pathway. Conclusion: Our study shows that CREG protected the kidney against HS-diet-induced renal damage and provides new insights into the mechanisms underlying kidney injury.

Network and 16S rRNA Sequencing-Combined Approach Provides Insightal Evidence of Vitamin K2 for Salt-Sensitive Hypertension

“…On the basis of understanding the interaction network of "drug-target-disease, " the intervention and influence of drugs on the complex pathological network were observed through network analysis, and the interaction relationship between each node of the network was observed intuitively and clearly by using large-scale data integration, which provided a new platform for the mechanism target research of complex diseases (13,14). The results of network pharmacology research showed that the core targets of VK2 in the treatment of salt-sensitive hypertension included as ALB, REN, IL10, SERPINE1, SRC, EGFR, F2, MAPK8, ESR1, and PLG.…”

“…The network construction of VK2-targets-pathways-disease network was conducted using Cytoscape_v3.7.1. The detailed methods were described in previous reports (13,14).…”

“…Network pharmacology is based on the principle of system biology to explain the process of disease, and further use the holistic view of network structure to understand the mechanisms of drug and disease. In recent years, as a hot method, it has been widely used in the analysis of drug mechanism (13,14). From the perspective of network pharmacology, the potential targets and mechanisms of VK2 on salt-sensitive hypertension were studied by using various database resources.…”

CREG Protects Retinal Ganglion Cells loss and Retinal Function Impairment Against ischemia-reperfusion Injury in mice via Akt Signaling Pathway

“…Similarly, Liu et al [11] indicated that the upregulation of CREG reduced human umbilical vein endothelial cells apoptosis induced by high glucose and high palmitate. Besides, a recent study found that administration of recombinant CREG prevented renal cell apoptosis and protected renal tissue against kidney injury and brosis with a high-salt diet [12]. Most recently, accumulating evidence revealed a critical role of CREG in ischemia-reperfusion injury [13].…”

CREG mitigates neonatal HIE injury through survival promotion and apoptosis inhibition in hippocampal neurons via activating AKT signaling

“…A recent study has identified that CREG overexpression suppresses pathological apoptosis in human vascular smooth muscle cells, which can be attributed to the activation of the vascular endothelial growth factor (VEGF)/PI3K/AKT signaling pathway (Wang et al, 2011). Similarly, recombinant CREG treatment inhibited apoptosis of the kidney cells, relieved renal fibrosis, and thereby improved renal function in high‐salt diet‐induced hypertensive nephropathy (Liu et al, 2020). The above background suggested CREG might play an essential role in neuronal apoptosis during neonatal HIE occurrence and development, which could possess the ability to contribute to neonatal HIE treatment.…”