Metadherin orchestrates PKA and PKM2 to activate ß-catenin signaling in podocytes during proteinuric chronic kidney disease.

Podocyte damage is the major cause of glomerular injury and proteinuria in multiple chronic kidney diseases. Metadherin (MTDH) is involved in podocyte apoptosis and promotes renal tubular injury in mouse models of diabetic nephropathy and renal fibrosis; however, its role in podocyte injury and proteinuria needs further exploration. Here, we show that MTDH was induced in the glomerular podocytes of patients with proteinuric chronic kidney disease and correlated with proteinuria. Podocyte-specific knockout of MTDH in mice reversed proteinuria, attenuated podocyte injury, and prevented glomerulosclerosis after advanced oxidation protein products challenge or adriamycin injury. Furthermore, specific knockout of MTDH in podocytes repressed ß-catenin phosphorylation at the Ser675 site and inhibited its downstream target gene transcription. Mechanistically, on the one hand, MTDH increased cAMP and then activated protein kinase A (PKA) to induce ß-catenin phosphorylation at the Ser675 site, facilitating the nuclear translocation of MTDH and ß-catenin; on the other hand, MTDH induced the deaggregation of pyruvate kinase M2 (PKM2) tetramers and promoted PKM2 monomers to enter the nucleus. This cascade of events leads to the formation of the MTDH/PKM2/ß-catenin/CBP/TCF4 transcription complex, thus triggering TCF4-dependent gene transcription. Inhibition of PKA activity by H-89 or blockade of PKM2 deaggregation by TEPP-46 abolished this cascade of events and disrupted transcription complex formation. These results suggest that MTDH induces podocyte injury and proteinuria by assembling the ß-catenin-mediated transcription complex by regulating PKA and PKM2 function.

Renal Fibrosis Is Alleviated through Targeted Inhibition of IL-11-Induced Renal Tubular Epithelial-to-Mesenchymal Transition.

Renal fibrosis is a pathologic process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in this process. The current study found that aberrant expression of IL-11 is critically involved in tubular EMT. IL-11 and its receptor subunit alpha-1 (IL-11Rα1) were significantly induced in renal tubular epithelial cells (RTECs) in unilateral ureteral obstruction (UUO) kidneys, co-localized with transforming growth factor-ß1. IL-11 knockdown ameliorated UUO-induced renal fibrosis in vivo and transforming growth factor-ß1-induced EMT in vitro. IL-11 intervention directly induced the transdifferentiation of RTECs to the mesenchymal phenotype and increased the synthesis of profibrotic mediators. The EMT response induced by IL-11 was dependent on the sequential activation of STAT3 and extracellular signal-regulated kinase 1/2 signaling pathways and the up-regulation of metadherin in RTECs. Micheliolide (MCL) competitively inhibited the binding of IL-11 with IL-11Rα1, suppressing the activation of STAT3 and extracellular signal-regulated kinase 1/2-metadherin pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide, a pro-drug of MCL for in vivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in the UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and that MCL/dimethylaminomicheliolide exerts its antifibrotic effect by suppressing IL-11/IL-11Rα1 interaction and blocking its downstream effects.

[Value of biochemical marker detection in risk stratification in patients with acute coronary syndrome].

OBJECTIVE: To assess the value of biochemical marker detection in risk stratification in hospitalized patients with acute coronary syndrome (ACS). METHODS: A total of 264 consecutive patients (180 male and 84 female patients) admitted for complaint of chest tightness or/and pain were evaluated for a decision of coronary angiography (CAG) within 24 h after admission. The patients were divided into two groups to receive emergency or elective CAG. The venous blood samples were taken from the patient immediately after admission for detection of amino-terminal pro-brain natriuretic peptide (NT-pro-BNP), high-sensitivity C-reactive protein (hs-CRP), myeloperoxidase (MPO), monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule (sICAM-1), soluble CD40 ligand (sCD40L), matrix metalloproteinase 9 (MMP-9), interleukin-6 (IL-6), interleukin 27 (IL-27) and creatine kinase isoenzyme (CK-MB) were detected. RESULTS: No significant differences in NT-proBNP, hs-CRP, MPO, sCD40L, and MMP-9 were found between emergency CAG group and elective CAG group (P<0.05). Logistic regression identified significant differences in NT-proBNP, hs-CRP, MPO, IL-27 and CK-MB between the two groups, and a predictive model for risk stratification of ACS was established using these biomarkers. The ROC curves of this predictive model showed an area under the curve of 98.1, suggesting a high predictive value of this model in assessment of the changes or progression of ACS. CONCLUSION: Combined detection of the biochemical markers can be helpful for risk stratification of the hospitalized patients with ACS early after admission.