Ischemic tubular injury: Oxygen-sensitive signals and metabolic reprogramming

TAX1BP1 regulates the apoptosis of renal tubular epithelial cells in ischemia/reperfusion injury via the NF-kB/PMAIP1 signaling pathway

RNA therapy involves utilizing RNA-based molecules to control biological pathways, aiming to cure specific diseases. As our understanding of RNA functions and their roles has expanded, the application of RNA therapies has broadened to target various therapeutic points. This approach holds promise for treating a range of diseases, including kidney diseases. Therapeutic RNA can be employed to target specific genes or pathways implicated in the development of kidney conditions, such as inflammation, fibrosis, and oxidative stress. This review highlights the therapeutic potential of RNA-based therapies across different types of kidney diseases, encompassing infection, inflammation, nephrotoxicity, and ischemia/reperfusion injury. Furthermore, studies have pinpointed the specific kidney cells involved in RNA therapy. To address challenges hindering the potential impact of RNA-based drugs on their targets, nanotechnology is integrated, and RNA-loaded vehicles with ligands are explored for more efficient outcomes. 

RNA therapeutics for kidney injury.

LncRNAs are reported to participate in multiple biological and pathological processes, including renal fibrosis due to obstructive nephropathy. However, the function and mechanisms of each lncRNA in this context differ. In this study, we created a fibrosis model in vitro using TGF-β1 treatment and in vivo through unilateral ureteral obstruction. We demonstrated that lncRNA6524 expression increased in both models, as confirmed by qPCR. Additionally, we discovered that lncRNA6524 mediates the TGF-β1-induced accumulation of extracellular matrix (ECM) proteins in BUMPT cells. We investigated the mechanism using dual luciferase reporter assays, immunofluorescence, and qPCR. Our results indicate that lncRNA6524 acts as a sponge for miR-92a-2-5p, promoting renal fibrosis by upregulating the Dvl1/Wnt/β-catenin signaling pathway. In summary, our findings demonstrate a linear regulatory relationship among lncRNA6524, miR-92a-2-5p, and the Dvl1/Wnt/β-catenin axis in renal epithelial cells during kidney obstruction. This highlights a new potential target for treating obstruction-related renal fibrosis. 

The LncRNA6524/miR-92a-2-5p/Dvl1/Wnt/β-catenin axis promotes renal fibrosis in the UUO mouse model

Abstract Acute kidney injury(AKI) has higher perioperative mortality and morbidity as well as high medical expense. Ischemia-reperfusion injury (I/R) is one of the most common causes of AKI.The molecular mechanism underlying I/R induced AKI is still unclarified, and there is a lack of early diagnosis markers. Herein, we demonstrated that mmu-lncRNA129814 was triggered by ischemic AKI in BUMPT cells and C57BL/6J mice. The knockdown of mmu-lncRNA129814 attenuated I/R-stimulated BUMPT cell death, and its overexpression had an opposite effect. Mechanistically, mmu-lncRNA129814 could sponge miRNA-494-5p and upregulated IL-1α expression to promote cell apoptosis. Furthermore, knockdown of mmu-lncRNA129814 ameliorated the I/R-induced progression of AKI via targeting miRNA-494-5p/IL-1α pathways. Interestingly, hsa-lncRNA582795, a homology with mmu-lncRNA129814, also promoted I/R-stimulated HK-2 cell apoptosis and AKI progression by regulating the miRNA-494-5p/IL-1α axis. Finally, we found that I/R-induced AKI patients exhibited remarkably elevated plasma and urinary levels of hsa-lncRNA582795 compared to those after Ischemia-reperfusion without AKI. Spearman’s test demonstrated a significant correlation between serum creatinine and plasma hsa-lncRNA582795 in I/R patients (r = 0.824),while urinary hsa-lncRNA582795 and urinary [TIMP2]*[IGFBP7]( r = 0.789). The AUC values of plasma and urinary hsa-lncRNA582795 were 0.889 and 0.804, respectively. The plasma hsa-lncRNA 582795 had a low specificity (86.7%) and high sensitivity (76.7%) compared to urinary hsa-lncRNA 582795 (93.3% and 63.3%, respectively). Collectively, the mmu-lncRNA129814/hsa-lncRNA582795/miRNA-494-5p/IL-1α axis was found to modulate the progression of ischemic AKI, and hsa-lncRNA582795 could act as a diagnosis biomarker and potential therapy target of I/R induced AKI. 

Discovery of mmu-lncRNA129814/hsa-lncRNA582795 as a potential biomarker and intervention target for ischemia reperfusion injury-induced AKI

Although recent studies have reported that long non-coding RNA (lncRNA) is involved in the development of ischemic acute kidney injury (AKI), the exact function and regulatory mechanism of lncRNAs in ischemic AKI remain largely unknown. Herein, we found that ischemic injury promoted the expression of lncRNA 148400 in mouse proximal tubule-derived cell line (BUMPT) and C57BL/6J mice. Furthermore, the lncRNA148400 mediates ischemic injury-induced apoptosis of BUMPT cells. Mechanistically, lncRNA 148400 sponged miR−10b−3p to promote apoptosis via GRK4 upregulation. Finally, knockdown of lncRNA 148400 alleviated the I/R-induced deterioration of renal function, renal tubular injury, and cell apoptosis. In addition, cleaved caspase−3 is increased via targeting the miR−10b−3p/GRK4 axis. Collectively, these results showed that lncRNA 148400/miR−10b−3p/GRK4 axis mediated the development of ischemic AKI.

/pdf/lncrna-148400-promotes-the-apoptosis-of-renal-tubular-17lnpljf.pdf

LncRNA 148400 Promotes the Apoptosis of Renal Tubular Epithelial Cells in Ischemic AKI by Targeting the miR−10b−3p/GRK4 Axis

Progressing from acute kidney injury (AKI) to chronic kidney disease (CKD) is acknowledged as a significant clinical challenge. Our recent works indicated that PR domain-containing 16 (PRDM16) impedes the progression of AKI and DKD. Nonetheless, the specific function and regulatory mechanism of PRDM16 during the AKI to CKD transition remain incompletely understood. In this investigation, it was identified that PRDM16 mitigates TGF-β1-induced renal tubulointerstitial fibrosis in BUMPT cells. From a mechanistic perspective, PRDM16 was found to enhance the expression of eif6, which subsequently suppressed TGF-β, CTGF, and NLRP3 levels via the suppression of the Wnt/β-catenin/SP1 signaling cascade. Additionally, knock-in of PRDM16 in kidney proximal tubules resulted in increased expression of eIF6, thereby restraining the stimulation of the Wnt/β-catenin/SP1 pathway, reducing the production of TGF-β, CTGF, and NLRP3, and consequently limiting renal tubulointerstitial fibrosis progression in both unilateral ureteral obstruction and ischemia–reperfusion-injury mouse models.Moreover, overexpression of PRDM16 following ischemia-induced AKI was shown to attenuate renal tubulointerstitial fibrosis and the eIF6/Wnt/β-catenin/SP1/TGF-β, CTGF, and NLRP3 axis. Finally, the PRDM16/eIF6/Wnt/β-catenin/SP1/TGF-β, CTGF, and NLRP3 axis were analyzed in renal biopsies from individuals with minimal change disease and severe obstructive nephropathy. Collectively, these findings indicate that PRDM16-mediated eIF6 induction serves to impede the transition from AKI to CKD by suppressing the Wnt/β-catenin/SP1/TGF-β, CTGF, and NLRP3 axis.

PRDM16 acts as a homeostasis regulation factor to suppress the transition of AKI to CKD via upregulation of eukaryotic initiation factor 6

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LncRNA 148400 Promotes the Apoptosis of Renal Tubular Epithelial Cells in Ischemic AKI by Targeting the miR−10b−3p/GRK4 Axis

PRDM16 acts as a homeostasis regulation factor to suppress the transition of AKI to CKD via upregulation of eukaryotic initiation factor 6