Membrane protease prostasin promotes insulin secretion by regulating the epidermal growth factor receptor pathway.

Prostasin (PRSS8) is a serine protease that metabolizes and moderates the effect of specific substrates. Epidermal growth factor receptor (EGFR), which modulates insulin secretion and pancreatic ß-cell proliferation, is regulated via proteolytic shedding by PRSS8. We first detected PRSS8 expression in ß-cells of pancreatic islets of mice. To better understand the molecular processes involved in PRSS8-associated insulin secretion, pancreatic ß-cell-specific PRSS8 knockout (ßKO) and PRSS8-overexpressing (ßTG) male mice were generated. We found that glucose intolerance and reduction in glucose-stimulated insulin secretion developed in ßKO mice compared with the control subjects. A higher response to glucose was noted in islets retrieved from ßTG mice. Erlotinib, a specific blocker of EGFR, blocks EGF- and glucose-stimulated secretion of insulin among MIN6 cells, and glucose improves EGF release from ß-cells. After silencing PRSS8 in MIN6 cells, glucose-stimulated insulin secretion decreased, and EGFR signaling was impaired. Conversely, overexpression of PRSS8 in MIN6 cells induced higher concentrations of both basal and glucose-stimulated insulin secretion and increased phospho-EGFR concentrations. Furthermore, short-term exposure to glucose improved the concentration of endogenous PRSS8 in MIN6 cells through inhibition of intracellular degradation. These findings suggest that PRSS8 is involved in glucose-dependent physiological regulation of insulin secretion via the EGF-EGFR signaling pathway in pancreatic ß-cells.

Prognostic Nutritional Index as a Predictor of Mortality in 101,616 Patients Undergoing Hemodialysis.

High mortality in dialysis patients is linked to malnutrition and inflammation. Prognostic nutritional index (PNI), calculated from serum albumin level and total lymphocyte count, has been developed as a prognostic marker for cancer patients. We investigated the clinical utility of PNI in predicting mortality in patients undergoing hemodialysis. Thus, 101,616 patients who initiated hemodialysis in United States dialysis centers between 2007 and 2011 were included in this retrospective cohort study. Using the Cox regression model, we assessed the relationship between PNI and mortality. Further, the predictive value of PNI for one-year mortality was compared with that of its constituent using area under the receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement. Higher PNI quartiles were incrementally associated with lower mortality; in patients with PNI values of 39.5−<43.1, 43.1−<46.6, and ≥46.6 (reference: PNI < 39.5), case-mix adjusted hazard ratios (95% confidence intervals) were 0.66 (0.64, 0.68), 0.49 (0.48, 0.51), and 0.36 (0.34, 0.37), respectively. PNI predicted mortality better than serum albumin level or total lymphocyte count alone. In the subgroup analysis, PNI performed well in predicting mortality in patients aged < 65 years. Our results indicate that PNI is a simple and practical prognostic marker in patients undergoing hemodialysis.

Associations between visceral obesity and renal impairment in health checkup participants: a retrospective cohort study.

BACKGROUND: Obesity is a risk factor for chronic kidney disease. Although body mass index (BMI) or waist circumference is indicators of obesity, actual measurements of visceral fat area (VFA) more accurately reflect the amount of visceral fat. We aimed to determine the most sensitive obesity indicator for predicting renal impairment among VFA, BMI, waist circumference, waist-to-height ratio, and visceral-to-subcutaneous fat ratio (VSR). METHODS: Subjects who underwent VFA measurements during health checkups in 2012 were included. Obesity was defined using a separate baseline value for each indicator [VFA (100 cm2), BMI (25 kg/m2), waist circumference (85 cm for men and 90 cm for women), waist-to-height ratio (0.5), VSR (0.4)]. Changes in estimated glomerular filtration rate (eGFRcr) and time to new-onset proteinuria were measured. The relationships between obesity indicators and eGFRcr were evaluated using a linear mixed-effects model. The relationships between obesity indicators and new-onset proteinuria were evaluated using Poisson regression analysis. RESULTS: Analysis was performed on 2753 subjects (mean age 50.3 years). The VFA ≥ 100 cm2 group exhibited a larger annual difference in eGFRcr compared to the < 100 cm2 group (- 0.24 mL/min/1.73 m2, P = 0.03). There was a statistically significant difference in the proteinuria incidence rate ratio, which was 1.54 times (95% confidence interval 1.01-2.35) in the VFA ≥ 100 cm2 group. Statistically significant correlations were not observed with any of the other obesity indicators. CONCLUSION: VFA is suggested to be the most sensitive obesity indicator for decline in kidney function and new-onset proteinuria.

Doxycycline attenuates cisplatin-induced acute kidney injury through pleiotropic effects.

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 antitumor, anti-inflammatory, antioxidative, 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 seven days of pretreatment with Dox, CDDP was administered and the animals were killed at day 1 or day 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.

Liddle's-like syndrome associated with nephrotic syndrome secondary to membranous nephropathy: the first case report.

BACKGROUND: Liddle'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) ß 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 PRESENTATION: A 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 ß or γ subunits of the ENaC gene was not identified. CONCLUSION: We 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.

Sirtuin 7 Deficiency Ameliorates Cisplatin-induced Acute Kidney Injury Through Regulation of the Inflammatory Response.

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.