Renal fibrosis is the main pathological characteristic of chronic kidney disease (CKD), whereas the underlying mechanisms of renal fibrosis are not clear yet. Herein, we found an increased expression of microRNA-34a (miR-34a) in renal tubular epithelial cells of patients with renal fibrosis and mice undergoing unilateral ureteral obstruction (UUO). In miR-34a À/À mice, miR-34a deficiency attenuated the progression of renal fibrosis following UUO surgery. The miR-34a overexpression promoted epithelial-to-mesenchymal transition (EMT) in cultured human renal tubular epithelial HK-2 cells, which was accompanied by sharp downregulation of Klotho, an endogenous inhibitor of renal fibrosis. Luciferase reporter assay revealed that miR-34a downregulated Klotho expression though direct binding with the 3 0 UTR of Klotho. Conversely, overexpression of Klotho prevented miR-34a-induced EMT in HK-2 cells. Furthermore, results showed that miR-34a was induced by transforming growth factor b1 (TGF-b1) through p53 activation, whereas dihydromyricetin could inhibit TGF-b1-induced miR-34a overexpression. Accordingly, dihydromyricetin administration dramatically restored the aberrant upregulation of miR-34a and Klotho reduction in obstructed kidney, and markedly ameliorated renal fibrosis in the Adriamycin nephropathy and UUO model mice. These findings suggested that miR-34a plays an important role in the progression of renal fibrosis, which provides new insights into the pathogenesis and treatment of CKD.

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Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.