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Excessive mitochondrial fission has been identified as the pathogenesis of diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation in the setting of DN remains unknown. In the current study, we found that dual-specificity protein phosphatase-1 (DUSP1) was actually downregulated by chronic hyperglycemia stimulus. Lower DUSP1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, defective DUSP1 expression activated JNK pathway, and the latter selectively opened mitochondrial fission by modulating mitochondrial fission factor (Mff) phosphorylation. Excessive Mff-related mitochondrial fission evoked mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria-dependent cellular apoptosis in the setting of diabetes. However, overexpression of DUSP1 interrupted Mff-related mitochondrial fission, reducing hyperglycemia-mediated mitochondrial damage and thus improving renal function. Overall, we have shown that DUSP1 functions as a novel malefactor in diabetic renal damage that mediates via modifying Mff-related mitochondrial fission. Thus, finding strategies to regulate the balance of the DUSP1-JNK-Mff signaling pathway and mitochondrial homeostasis may be a therapeutic target for treating diabetic nephropathy in clinical practice.

Ischemia is the most frequent cause of acute kidney injury (AKI), which is characterized by apoptosis of renal tubular cell. A common result of ischemia in AKI is dysfunction of endoplasmic reticulum (ER), which causes the protein-folding capacity to lag behind the protein-folding load. The abundance of misfolded proteins stressed the ER and results in induction of the unfolded protein response (UPR). While the UPR is an adaptive response, over time it can result in apoptosis when cells are unable to recover quickly. Recent research suggests that ER stress is a major factor in renal tubular cell apoptosis resulting from ischemic AKI. Thus, ER stress may be an important new progression factor in the pathology of ischemic AKI. In this article, we review UPR signaling, describe pathology and pathophysiology mechanisms of ischemic AKI, and highlight the dual function of ER stress on renal tubular cell apoptosis. ARTICLE HISTORY

ObjectivesTo evaluate differences in the health-related quality of life (HRQoL) between patients with constipation receiving hemodialysis (HD) and those receiving peritoneal dialysis (PD).MethodsIn this cross-sectional study, 605 dialysis patients (478 HD cases and 127 PD cases; all patients were older than 18 years) from our hospital were included. A questionnaire was used to evaluate their constipation statuses. The effect of constipation on HRQoL was assessed, using the Chinese version of the 12-item short-form (SF-12) general health survey. Karnofsky score, sociodemographic, and clinical data were also collected. We performed multiple logistic regression analysis to define independent risk factors for constipation and impaired HRQoL.ResultsA total of 605 participants (326 men [53.9%] and 279 women [46.1%]) were surveyed. The incidence of constipation was 71.7% in HD patients and 14.2% in PD patients. Dialysis patients with constipation had significantly lower mean SF-12 Physical Component Summary scale and Mental Component Summary scale scores than the nonconstipation group (P < 0.05), whereas HD patients had better SF-12 Physical Component Summary and Mental Component Summary scores than PD patients (P < 0.05). When we performed multivariate logistic regression analysis, dialysis modality, diabetes, and the number of constipation-related medications were three independent risk factors associated with constipation. As for impaired HRQoL in the constipated dialysis population, dialysis modality was found to be another independent risk factor in addition to age and diabetes.ConclusionPD patients with constipation had worse HRQoL than HD control participants. We should pay more attention to the patients with constipation receiving PD, as peritonitis caused by constipation was associated with a higher mortality.

The involvement of caspases in postmitotic cell death is controversial. Here we report that adult brain and heart are devoid of many key pro-apoptotic proteins due to a progressive postnatal silencing event involving a reduction of their transcript levels. E2F has been shown to control cell cycle progression and to be transcriptional activator of apoptotic genes. However, our data demonstrate that apoptotic gene expression in heart, brain and liver, as well as cardiac and neuronal apoptotic gene silencing during development, are E2F-independent events. Therefore, the genes regulating caspase-dependent cell death are expressed in embryonic organs in an E2F-independent manner and a developmental-related silencing event represses these genes in postmitotic adult tissues.