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Small-RNA sequencing of human urinary extracellular vesicles reveals association of high sodium diet with renal pro-inflammatory pathways

ABSTRACT: Background High sodium intake is associated with arterial hypertension and cardiovascular disease, through mechanisms that go beyond hemodynamic changes, including endothelial dysfunction, oxidative stress, and induction of a pro-inflammatory milieu. The aim of this study was to assess the role of dietary sodium modulation on renal pathophysiology through evaluation of small RNA cargos on urinary extracellular vesicles (uEVs). Methods Fourteen high-risk normotensive subjects with normal kidney function were prospectively enrolled to undergo a low sodium diet (LSD) followed by high sodium diet (HSD). The uEVs were isolated from a 24h urine collection at the end of each diet phase and profiled by small RNA sequencing. Selected differentially expressed microRNAs (miRNAs) were validated in human proximal tubular cell line (HK-2 cells) to assess miRNA-mRNA target interactions. Results We identified 111 small RNA species of which 30 were significantly different between LSD and HSD. Bioinformatic network analysis showed that pathways related to the innate and adaptive immune system, interleukin and interferon signalling were enriched in HSD, whereas pathways related to peroxisome proliferator-activated receptor alpha (PPARα) regulation were enriched in LSD. In HK-2 cells, the inhibition of miR-320b, down-regulated in HSD, increased intercellular adhesion molecule 1 (ICAM-1), with renal pro-inflammatory effects. The inhibition of miR-10b-5p, down-regulated in LSD, increased PPARα, which has an anti-fibrotic and anti-inflammatory role in the kidney. Conclusions Small RNA characterization from uEVs revealed that HSD is associated with pro-inflammatory changes, potentially contributing to sodium-induced low-grade renal inflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288935 | GEO | 2025/12/12

REPOSITORIES: GEO

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Project description:Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide with limited treatment options. The intricate pathogenesis of dysregulated lipid metabolism leading to the development of DKD remains obscure. Lipophagy, which refers to the autophagic degradation of intracellular lipid droplets, has been found to be impaired in DKD, resulting in renal tubule dysfunction and ectopic lipid deposition (ELD). The lipotoxity in renal tubules is closely related to the pathogenesis of DKD. Therefore, it is crucial to develop effective and safe agents that can restore autophagic flux and lipophagy in renal tubules for potential preventive interventions. Purpose: This study seeks to investigate the preventive effect of sodium butyrate (NaB) on ELD in the progression of DKD and elucidate the underlying mechanisms involved.Methods: The beneficial effects of NaB were investigated in glucolipotoxicity (GLT)-stimulated HK-2 cells and the streptozotocin (STZ) injection combined with a high-fat diet induced DKD model mice. Additionally, we managed to silence transcription factor EB (TFEB) in HK-2 cells and establish the renal specific silence model by retrograde ureteral infusion of AAV9-shTFEB in mice. We investigated the expression profile of RNAs in HK-2 cells through. The mechanism of NaB is demonstrated by RNA sequencing (RNA-seq), pulldown MS assay, SPR experiments etc.Results: Our findings revealed that serum butyrate level is reduced in DKD patients and is statistically correlated with urinary protein excretion and eGFR. Sodium butyrate (NaB) dose-dependently improved lipid deposition in HK-2 cells and renal tubular epithelial cells of DKD model mice. This effect may be attributed to the promotion of TFEB dephosphorylation, as NaB can directly interact with PPP2R1A to activate PP2A phosphorylation activity. Therefore, NaB may play a role in improving renal lipid deposition in DKD through the PP2A-TFEB pathway. Conclusion: NaB acts as a PP2A-TFEB axis activator that restores lipophagy to ameliorate ELD and renal dysfunction in DKD.

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Small-RNA sequencing of human urinary extracellular vesicles reveals association of high sodium diet with renal pro-inflammatory pathways

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