OBJECTIVEDiabetic nephropathy is one of the major causes of renal failure, which is accompanied by the production of reactive oxygen species (ROS). Nrf2 is the primary transcription factor that controls the antioxidant response essential for maintaining cellular redox homeostasis. Here, we report our findings demonstrating a protective role of Nrf2 against diabetic nephropathy.RESEARCH DESIGN AND METHODSWe explore the protective role of Nrf2 against diabetic nephropathy using human kidney biopsy tissues from diabetic nephropathy patients, a streptozotocin-induced diabetic nephropathy model in Nrf2−/− mice, and cultured human mesangial cells.RESULTSThe glomeruli of human diabetic nephropathy patients were under oxidative stress and had elevated Nrf2 levels. In the animal study, Nrf2 was demonstrated to be crucial in ameliorating streptozotocin-induced renal damage. This is evident by Nrf2−/− mice having higher ROS production and suffering from greater oxidative DNA damage and renal injury compared with Nrf2+/+ mice. Mechanistic studies in both in vivo and in vitro systems showed that the Nrf2-mediated protection against diabetic nephropathy is, at least, partially through inhibition of transforming growth factor-β1 (TGF-β1) and reduction of extracellular matrix production. In human renal mesangial cells, high glucose induced ROS production and activated expression of Nrf2 and its downstream genes. Furthermore, activation or overexpression of Nrf2 inhibited the promoter activity of TGF-β1 in a dose-dependent manner, whereas knockdown of Nrf2 by siRNA enhanced TGF-β1 transcription and fibronectin production.CONCLUSIONSThis work clearly indicates a protective role of Nrf2 in diabetic nephropathy, suggesting that dietary or therapeutic activation of Nrf2 could be used as a strategy to prevent or slow down the progression of diabetic nephropathy.

No abstract

Acute kidney injury (AKI) is associated with significant morbidity and its chronic inflammation contributes to subsequent chronic kidney disease (CKD) development. Yes-associated protein (YAP), the major transcriptional coactivator of the Hippo pathway, has been shown associated with chronic inflammation, but its role and mechanism in AKI-CKD transition remain unclear. Here we aimed to investigate the role of YAP in AKI-induced chronic inflammation. Renal ischemia/reperfusion (I/R) was used to induce a mouse model of AKI-CKD transition. We used verteporfin (VP), a pharmacological inhibitor of YAP, to treat post-IRI mice for a period, and evaluated the influence of YAP inhibition on long-term outcomes of AKI. In our results, severe IRI led to maladaptive tubular repair, macrophages infiltration, and progressive fibrosis. Following AKI, the Hippo pathway was found significantly altered with YAP persistent activation. Besides, tubular YAP activation was associated with the maladaptive repair, also correlated with interstitial macrophage infiltration. Monocyte chemoattractant protein 1 (MCP-1) was found notably upregulated with YAP activation. Of note, pharmacological inhibition of YAP in vivo attenuated renal inflammation, including macrophage infiltration and MCP-1 overexpression. Consistently, in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) induced YAP activation and MCP-1 overproduction whereas these could be inhibited by VP. In addition, we modulated YAP activity by RNA interference, which further confirmed YAP activation enhances MCP-1 expression. Together, we concluded tubular YAP activation with maladaptive repair exacerbates renal inflammation probably via promoting MCP-1 production, which contributes to AKI-CKD transition.

No abstract

Kaposi’s sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS) as well as two lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman’s disease. KSHV encodes viral proteins, such as K1, that alter signaling pathways involved in cell survival. Expression of K1 has been reported to transform rodent fibroblasts, and K1 transgenic mice develop multiple tumors, suggesting that K1 has an important role in KSHV pathogenesis. We found that cells infected with a KSHV virus containing a WT K1 gene had a survival advantage under conditions of nutrient deprivation compared to cells infected with KSHV K1 mutant viruses. 5’ adenosine monophosphate-activated protein kinase (AMPK) responds to nutrient deprivation by maintaining energy homeostasis, and AMPK signaling has been shown to promote cell survival in various types of cancers. Under conditions of AMPK inhibition, we also observed that cells infected with KSHV containing a WT K1 gene had a survival advantage compared to KSHV K1 mutant virus infected cells. To explore the underpinnings of this phenotype, we identified K1-associated cellular proteins by tandem affinity purification and mass spectrometry. We found that the KSHV K1 protein associates with the gamma subunit of AMPK (AMPKγ1). We corroborated this finding by independently confirming that K1 co-immunoprecipitates with AMPKγ1. Co-immunoprecipitations of wild-type K1 (K1WT) or K1 domain mutants and AMPKγ1, revealed that the K1 N-terminus is important for the association between K1 and AMPKγ1. We propose that the KSHV K1 protein promotes cell survival via its association with AMPKγ1 following exposure to stress.