Protective effect of phosphoenolpyruvate carboxykinase 1 on inflammation and fibrotic progression of IgA nephropathy.

INTRODUCTION: Phosphoenolpyruvate carboxykinase 1 (PCK1) is an essential enzyme of the gluconeogenic pathway, which can affect kidney physiology in various ways. Nevertheless, its role in the progression of IgA nephropathy (IgAN) remains to be elucidated. METHODS: We identified the differentially expressed genes in the glomeruli of IgAN patients through weighted gene co-expression network analysis across three datasets. Through clinical renal pathological tissue and cellular experiments, we further validated the gene and investigated its relationship with the inflammatory markers and fibrosis indicators in IgAN. RESULTS: Compared to peritumoral normal tissues, the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway have been identified as key elements in IgAN pathogenesis from two GEO databases and a validation dataset. PCK1 was identified and validated as one of the most promising candidate genes. The expression of PCK1 in clinically collected kidney specimens was significantly downregulated in patients with IgAN compared to healthy controls. The expression of PCK1 was inversely correlated with clinical indicators such as urinary albumin-to-creatinine ratio, 24-hour proteinuria. In experiments with SV40-transformed mouse glomerular mesangial cells (MCs), PCK1 and PPARγ protein expression levels were significantly decreased in polymeric IgA1 (pIgA1)-stimulated MCs, which contrasts with the increased expression of inflammatory and fibrotic factors. Overexpression of PCK1 inhibited cellular inflammation and fibrotic changes induced by pIgA1, demonstrating protective effects against cellular fibrosis similar to rosiglitazone. CONCLUSION: PCK1 exerted a pronounced inhibitory effect on mesangial cell inflammatory markers and fibrosis indicators in IgAN, potentially offering a novel therapeutic target for its treatment.