The effects of high-fat diet (HFD) and postprandial endotoxemia on the development of type 2 diabetes are not fully understood. Here we show that the serine protease prostasin (PRSS8) regulates hepatic insulin sensitivity by modulating Toll-like receptor 4 (TLR4)-mediated signalling. HFD triggers the suppression of PRSS8 expression by inducing endoplasmic reticulum (ER) stress and increases the TLR4 level in the liver. PRSS8 releases the ectodomain of TLR4 by cleaving it, which results in a reduction in the full-length form and reduces the activation of TLR4. Liver-specific PRSS8 knockout (LKO) mice develop insulin resistance associated with the increase in hepatic TLR4. Restoration of PRSS8 expression in livers of HFD, LKO and db/db mice decreases the TLR4 level and ameliorates insulin resistance. These results identify a novel physiological role for PRSS8 in the liver and provide new insight into the development of diabetes resulting from HFD or metabolic endotoxemia.
Cisplatin-induced acute kidney injury (AKI) has been recognized as one of cisplatin’s serious side effects, limiting its use in cancer therapy. Sirtuin 1 (SIRT1) and SIRT3 play protective roles against cisplatin-induced kidney injury. However, the role of SIRT7 in cisplatin-induced kidney injury is not yet known. In this study, we found that Sirt7 knockout (KO) mice were resistant to cisplatin-induced AKI. Furthermore, our studies identified that loss of SIRT7 decreases the expression of tumor necrosis factor-α (TNF-α) by regulating the nuclear expression of the transcription factor nuclear factor kappa B. It has been reported that cisplatin-induced nephrotoxicity is mediated by TNF-α. Our results indicate that SIRT7 plays an important role in cisplatin-induced AKI and suggest the possibility of SIRT7 as a novel therapeutic target for cisplatin-induced nephrotoxicity.
BackgroundLiddle’s syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel (ENaC) β or γ subunits. Patients with this syndrome present with early onset of hypertension, hypokalemia, metabolic alkalosis, hyporeninemia and hypoaldosteronism, and a potassium-sparing diuretics (triamterene or amiloride) can drastically improves the disease condition. Although elderly patients having these characteristics were considered to have Liddle’s syndrome or Liddle’s-like syndrome, no previous report has indicated that Liddle’s-like syndrome could be caused by nephrotic syndrome of primary glomerular disease, which is characterized by urinary excretion of > 3 g of protein/day plus edema and hypoalbuminemia, or has explained how the activity function of ENaC could be affected in the setting of high proteinuria.Case presentationA 65-year-old Japanese man presented with nephrotic syndrome. He had no remarkable family history, but had a medical history of hypertension and hyperlipidemia. On admission, hypertension, spironolactone-resistant hypokalemia (2.43 mEq/l), hyporeninemic hypoaldosteronism, and metabolic alkalosis, which suggested Liddle’s syndrome, were observed. Treatment with triamterene together with a steroid for nephrotic syndrome resulted in rapid and remarkable effective on improvements of hypertension, hypokalemia, and edema of the lower extremities. Renal biopsy revealed membranous nephropathy (MN) as the cause of nephrotic syndrome, and advanced gastric cancer was identified on screening examination for cancers that could be associated with the development of MN. After total gastrectomy, triamterene was not required and proteinuria decreased. A mutation in the β or γ subunits of the ENaC gene was not identified.ConclusionWe reported for the first time a case of Liddle’s-like syndrome associated with nephrotic syndrome secondary to MN. Aberrant activation of ENaC was suggested transient during the period of high proteinuria, and the activation was reversible with a decrease in proteinuria.
Cisplatin (CDDP) is a widely-used chemotherapeutic drug for solid tumors, but its nephrotoxicity is a major dose-limiting factor. Doxycycline (Dox) is a tetracycline antibiotic that has been commonly used in a variety of infections. Dox has been shown to possess several other properties, including anti-tumor, anti-inflammatory, anti-oxidative, and matrix metalloproteinase (MMP)-inhibiting actions. We therefore investigated whether Dox exerts renoprotective effects in CDDP-induced acute kidney injury (AKI). Twelve-week-old male C57BL/6J mice were divided into the following groups: 1) Control, 2) Dox (2 mg/ml in drinking water), 3) CDDP (25 mg/kg body weight, intraperitoneally), and 4) CDDP+Dox. After 7 days of pretreatment with Dox, CDDP was administered and the animals were sacrificed at day 1 or 3. We evaluated renal function along with renal histological damage, inflammation, oxidative stress, and apoptosis. MMP and serine protease activities in the kidney tissues were assessed using zymography. Administration of CDDP exhibited renal dysfunction and caused histological damage predominantly in the proximal tubules. Dox did not affect either expression of CDDP transporters or the accumulation of CDDP in renal tissues; however, it significantly ameliorated renal dysfunction and histological changes together with reduced detrimental responses such as oxidative stress and inflammation in the kidneys. Furthermore, Dox inhibited the activity of MMP-2 and MMP-9, as well as serine proteases in the kidney tissues. Finally, Dox markedly mitigated apoptosis in renal tubules. Thus, Dox ameliorated CDDP-induced AKI through its pleiotropic effects. Our results suggest that Dox may become a novel strategy for the prevention of CDDP-induced AKI in humans.
Background Serial management of renal anemia using continuous erythropoietin receptor activator (CERA) throughout the peritoneal dialysis initiation period has rarely been reported. We investigated the efficacy and dosage of CERA treatment from pre- to post-peritoneal dialysis initiation for anemia management in patients with end-stage renal disease. Methods Twenty-six patients (13 men; mean age 60.9 years) who started peritoneal dialysis between April 2012 and April 2018 were investigated. Serial changes in hemoglobin levels, transferrin saturation and ferritin levels, CERA dosage, and the erythropoietin resistance index (ERI) over a 48 week period were retrospectively examined. Results Mean hemoglobin levels increased significantly from 10.5 g/dL at 24 weeks prior to the peritoneal dialysis initiation to 11.5 g/dL at 4 weeks post-initiation. The proportion of patients with hemoglobin levels ≥ 11 g/dL increased significantly after peritoneal dialysis initiation. The mean CERA dosage was 57.0 µg/month at 24 weeks prior to dialysis initiation, 86.5 µg/month at initiation, and 72.0 µg/month at 4 weeks post-initiation. Thus, the dosage tended to increase immediately before peritoneal dialysis initiation and then decreased thereafter. Hemoglobin levels were significantly lower, while the CERA dosage for maintaining hemoglobin levels and ERI tended to be higher at dialysis initiation in patients with diabetes than in those without diabetes. Conclusion Treatment with CERA prior to and during the peritoneal dialysis initiation achieved fairly good anemia management in patients with and without diabetes. The CERA dosage could be reduced in patients without diabetes after dialysis initiation.
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