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Effect of interfering Itgb6 gene expression on renal proximal tubular epithelial cells during hypoxia/reoxygenation injury

ABSTRACT: Integrin αvβ6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by inflammatory-related side effects. Here, we revealed that upregulated αvβ6 in proximal tubule cells (PTCs) is remarkably positively correlated with renal inflammation both in CKD patients and in murine model of ischemia-reperfusion injury (IRI)-induced renal fibrosis. Knockout of αvβ6 significantly reduced the inflammatory response in IRI kidneys, especially the infiltration of pro-inflammatory macrophages. To delve deeper into the mechanism by which αvβ6 modulates inflammatory response, an unbiased RNA-sequencing of si-NC and si-Itgb6-transfected hypoxic TKPTS cells was performed.

ORGANISM(S): Mus musculus

PROVIDER: GSE253494 | GEO | 2024/01/18

REPOSITORIES: GEO

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Project description:We aimed to identify miRNA biomarkers of renal injury in kidney biopsies from patients with lupus nephritis. MiRNA profiles of 8 patients were analyzed for correlation with various clinical features including Progression, Activity, Chronicity, and Time to Kidney Failure. MicroRNAs (miRs) are promising biomarkers and are involved in pathogenesis of kidney diseases. We aimed to identify miR biomarkers of renal injury in kidney biopsies from patients with lupus nephritis and study their potential role in renal fibrosis. miR-150 was significantly increased in kidneys with high chronicity compared to low chronicity and it correlated positively with chronicity index scores and renal collagen I expression. In kidneys with high chronicity, miR-150 was found predominantly in proximal tubular cells (PTCs) and was moderately expressed in podocytes and to lesser degree in mesangial cells (MCs). We hypothesized that miR-150 increases fibrosis by downregulating a negative regulator of profibrotic proteins. Suppressor of cytokine signaling1 (SOCS1) is a predicted target of miR-150 and has shown antifibrotic role. After confirming that SOCS1 is a direct target of miR-150, we showed that transfection of a miR-150 analog downregulated SOCS1 protein and upregulated the profibrotic proteins fibronectin, collagen I, collagen III, and TGF-β1 in both primary normal human renal PTCs and MCs. A similar effect was seen when using a SOCS1 siRNA to confirm that the effect of miR-150 on profibrotic proteins is mediated through SOCS1. Stimulation with TGF-β1 induced miR-150 increase in PTCs and human podocytes but not MCs. These results suggest that miR-150 might be a useful quantitative renal biomarker of kidney injury in lupus nephritis and that miR-150, which might be partially induced by TGF-β1, plays an important role in renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1. FFPE kidney specimens (n=25) including baseline and repeated needle renal biopsies were from 14 patients with LN enrolled in IRB-approved protocols at the NIDDK between 1976 and 1999. The specimens were divided in two groups based on histological chronicity index (CI). CI ≥ 4 were categorized as having high degree of chronicity of chronic kidney injury. 18 kidneys from 8 patients including high CI (n=9) and low CI (n=9) were used for miR profiling by Affymetrix microRNA microarrays.

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Effect of interfering Itgb6 gene expression on renal proximal tubular epithelial cells during hypoxia/reoxygenation injury

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