Inhibition of IRE1/JNK pathway in HK-2 cells subjected to hypoxia-reoxygenation attenuates mesangial cells-derived extracellular matrix production.

Endoplasmic reticulum (ER) stress and inflammatory responses play active roles in the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). Inositol-requiring enzyme 1 (IRE1) activates c-Jun NH2 -terminal kinase (JNK) in ER stress. Tubular epithelial cells (TEC) are the main injury target and source of AKI inflammatory mediators. TEC injury may lead to glomerulosclerosis, however, the underlying mechanism remains unclear. Here, hypoxia/reoxygenation (H/R) HK-2 cells were used as an AKI model. To determine the partial effects of TEC injury on the glomerulus, HK-2 cells after H/R were co-cultured with human renal mesangial cells (HRMC). H/R up-regulated ER stress, IRE1/JNK pathway, IL-6 and MCP-1 in HK-2 cells. Stimulation of HRMC with IL-6 enhanced their proliferation and the expression of glomerulosclerosis-associated fibronectin and collagen IV via signal transducer and activator of transcription 3 (STAT3) activation. Similar responses were observed in HRMC co-cultured with HK-2 cells after H/R. IRE1/JNK inhibition reversed these injury responses in HRMC. IRE1/JNK stable knock-down in HK-2 cells and shRNA-mediated STAT3 depletion in HRMC confirmed their role in inflammation/glomerulosclerosis. These findings suggest that IRE1/JNK pathway mediates inflammation in TEC, affecting mesangial cells. The inhibition of this pathway could be a feasible approach to prevent AKI-CKD transition.

Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy.

Cytochrome c oxidase 20 (COX20)/FAM36A encodes a conserved protein that is important for the assembly of COX, complex IV of the mitochondrial respiratory chain. A homozygous mutation (p.Thr52Pro) in COX20 gene has been previously described to cause muscle hypotonia and ataxia. In this study, we describe two patients from a non-consanguineous family exhibiting autosomal recessive sensory-dominant axonal neuropathy and static encephalopathy. The whole-exome sequencing analysis revealed that both patients harbored compound heterozygous mutations (p.Lys14Arg and p.Trp74Cys) of COX20 gene. The pathogenicity of the variants was further supported by morphological alternations of mitochondria observed in sural nerve and decreased COX20 protein level of peripheral blood leucocytes derived from the patients. In conclusion, COX20 might be considered as a candidate gene for the complex inherited disease. This observation broadens the clinical and genetic spectrum of COX20-related disease. However, due to the limitation of a single-family study, additional cases and studies are definitely needed to further confirm the association.