Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice

Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow–derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD

The Japanese Clinical Practice Guideline for acute kidney injury 2016

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search

The eNOS-NO pathway attenuates kidney dysfunction via suppression of inflammasome activation in aldosterone-induced renal injury model mice.

Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction

Dipeptidyl peptidase-4 inhibitor linagliptin reduces urinary albumin excretion through the protection of glomerular endothelial function

　Background: In most developed countries, diabetic kidney disease is the most common cause of chronic kidney disease, leading to end-stage renal disease, and it is also associated with cardiovascular diseases, including heart failure, and a higher risk of other microvascular complications. A recent clinical trial indicated that the dipeptidyl peptidase-4 inhibitor linagliptin prevents the occurrence and progression of albuminuria in patients with type 2 diabetes. Thus, this study aimed to elucidate the molecular mechanism underlying the inhibitory effect of linagliptin on albuminuria in diabetic kidney disease. Methods: Control C57BL/6 mice and diabetic Ins2+/Akita mice were orally administered linagliptin (5 mg/kg/ day) every day for 8 weeks. Results: Compared to control mice, Ins2+/Akita mice had markedly elevated blood glucose and HbA1c levels, but there were no significant changes after linagliptin treatment. Furthermore, albuminuria and urinary 8-OHdG levels were significantly increased and glomerular mesangial area was significantly expanded in Ins2+/Akita mice compared to those in control mice; these changes were ameliorated by linagliptin treatment, which also improved the degradation of glomerular endothelial glycocalyx and enhancement of glomerular permeability of macromolecules. The activity of AMP-activated protein kinase and the expression of guanosine 5\u27-triphosphate cyclohydrolase I in human glomerular endothelial cells were significantly lower in high glucose conditions and were improved by linagliptin or GLP-1 administration. Discussion: These results together suggest that linagliptin reduced albuminuria in a blood glucose-independent manner via the reduction of oxidative stress and maintenance of the glycocalyx in endothelial cells. Thus, earlier treatment with linagliptin may slow the progression of diabetic kidney disease

髄膜炎による脳血管攣縮後に生じた中膜筋細胞壊死

金沢大学医薬保健研究域医学系金沢大学附属病院脳神経外科Light and electron microscopic studies were conducted on myonecrosis following cerebral arterial spasm in meningitis. A 34-year-old female developed fever, headache and vomiting. Neurological examination revealed a drowsy state, nuchal stiffness and hemiparesis. Spinal puncture revealed a purulent fluid containing 1,219/mm3 cells. She deteriorated steadily into semicoma 10 days after onset. Computerized tomography scan showed low density areas in bilateral basal ganglia and cerebellar hemispheres. Angiography showed vasospasm of the major cerebral arteries and vasodilatation of the left Sylvian arteries. Repeated angiography two months after onset showed a diffuse narrowing of these arteries. She died of uncal herniation 67 days after onset. Autopsy two hours after death disclosed softening in the territories of spastic arteries. Microscopically, the circle of Willis showed concentric stenosis due to an intimal proliferation. The media was remarkably atrophied and fibrotic with an infiltration of polymorphonuclear leucocytes. Electron-microscopically, the media disclosed numerous degenerating or necrotic smooth-muscle cells. The degenerating cells showed dissolution of myofilaments with resultant fine granular or filamentous material. The necrotic cells were abundant in vacuoles, lysosomes and dense bodies. The cytoplasm was eventually replaced by cellular debris and numerous collagen fibrils