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Tofogliflozin Attenuates Renal Lipid Deposition and Inflammation via PPARα restoration in Diet-induced Steatohepatitic mice. (RNA-Seq)

ABSTRACT: Aims: We have previously demonstrated hepatic, cardiac, and skin inflammation in high-fat diet-induced steatotic liver disease model. However, the molecular mechanism in the kidney in this model is still not clear. It has been recently reported that SGLT2 inhibitors improved chronic kidney disease (CKD). Therefore, we evaluated the effect of tofogliflozin on renal lipid metabolism and inflammation in this model. Methods: Male 8-10-week-old C57Bl/6 mice were fed high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or HF/HC/HS/BA diet alone (Cont group). After eight weeks, serum lipid profiles and histology, lipid content, mRNA/microRNA and protein expression levels in the kidney were examined. Results: The Tofo group showed significant reduction in body weight (26.9±0.9 vs 24.5±1.0 g; p<0.001) and kidney weight compared to the Cont group. Renal cholesterol (9.1±1.6 vs 7.5±0.7 mg/g; p<0.05) and non-esterified fatty acid (NEFA) (12.0±3.0 vs 8.4±1.5 µEq/g; p<0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed a decreasedd number of lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. microRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Interestingly, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and CPT1 in the Tofo group. Conclusions: Tofogliflozin decreased renal cholesterol and NEFA content and improved inflammation through the regulation of PPARα and miR-21a.

ORGANISM(S): Mus musculus

PROVIDER: GSE251737 | GEO | 2025/02/05

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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Tofogliflozin Attenuates Renal Lipid Deposition and Inflammation via PPARα restoration in Diet-induced Steatohepatitic mice. (RNA-Seq)

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