Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2 +/-) mice had no evidence of increased renal disease, and Ampka2 -/-mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity. IntroductionComplications of diabetes, including retinopathy, neuropathy, and nephropathy, are responsible for considerable morbidity, and are experienced by a majority of individuals with diabetes over time. How elevated glucose levels initiate these complications remains unclear. The prevailing theory states that enhanced mitochondrial production of superoxide anion in response to elevated cellular glucose concentrations leads to pathological pathway activation and cell dysfunction (1, 2). Studies in cell culture systems demonstrated that addition of high glucose produced an increase in ROS that has been attributed to the mitochondrial electron transport chain (ETC). The currently accepted scheme is that chronically elevated glucose leads to increased ROS production by mitochondria, contributing to downstream cellular injury processes, and ultimately resulting in end-organ dysfunction and structural changes. Based on this theory, numerous strategies are being developed to interrupt the mitochondrial production of superoxide and inhibit downstream deleterious pathways.

Fungi are major contributors to the opportunistic infections that affect patients with HIV/AIDS. Systemic infections are mainly with Pneumocystis jirovecii (pneumocystosis), Cryptococcus neoformans (cryptococcosis), Histoplasma capsulatum (histoplasmosis), and Talaromyces (Penicillium) marneffei (talaromycosis). The incidence of systemic fungal infections has decreased in people with HIV in high-income countries because of the widespread availability of antiretroviral drugs and early testing for HIV. However, in many areas with high HIV prevalence, patients present to care with advanced HIV infection and with a low CD4 cell count or re-present with persistent low CD4 cell counts because of poor adherence, resistance to antiretroviral drugs, or both. Affordable, rapid point-of-care diagnostic tests (as have been developed for cryptococcosis) are urgently needed for pneumocystosis, talaromycosis, and histoplasmosis. Additionally, antifungal drugs, including amphotericin B, liposomal amphotericin B, and flucytosine, need to be much more widely available. Such measures, together with continued international efforts in education and training in the management of fungal disease, have the potential to improve patient outcomes substantially.

Penicilliosis incidence correlates with the HIV/AIDS epidemic in Viet nam. The number of cases increases during rainy months. Injection drug use, shorter history, absence of fever or skin lesions, respiratory difficulty, higher lymphocyte count, and lower platelet count predict poor in-hospital outcome.

AMP-activated protein kinase (AMPK) is an important energy sensor that may be critical in regulating renal lipid accumulation. To evaluate the role of AMPK in mediating renal lipid accumulation, C57BL/6J mice were randomized to a standard diet, a high-fat diet, or a high-fat diet plus AICAR (an AMPK activator) for 14 weeks. Renal functional and structural studies along with electron microscopy were performed. Mice given the high-fat diet had proximal tubule injury with the presence of enlarged clear vacuoles, and multilaminar inclusions concurrent with an increase of tissue lipid and overloading of the lysosomal system. The margins of the clear vacuoles were positive for the endolysosomal marker, LAMP1, suggesting lysosome accumulation. Characterization of vesicles by special stains (Oil Red O, Nile Red, Luxol Fast Blue) and by electron microscopy showed they contained onion skin-like accumulations consistent with phospholipids. Moreover, cholesteryl esters and phosphatidylcholine-containing phospholipids were significantly increased in the kidneys of mice on a high-fat diet. AMPK activation with chronic AICAR treatment prevented the clinical and structural effects of high-fat diet. Thus, high-fat diet contributes to a dysfunction of the lysosomal system and altered lipid metabolism characterized by cholesterol and phospholipid accumulation in the kidney. AMPK NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript activation normalizes the changes in renal lipid content despite chronic exposure to lipid challenge. KeywordsAMPK; chronic kidney disease; lipid accumulation; lysosomal dysfunction; obesityThe growing epidemic of obesity particularly in the western world is considered a serious health and economic burden. Central obesity is a major risk factor for diabetes and hypertension that together account for ~ 70% of all cases of end-stage renal disease 1 that will lead to expensive renal replacement therapy. Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses in targeted organs. However, a full understanding of the mechanisms involved in progressive renal disease is still absent. Obesity-and diabetes-related kidney disease are associated with renal hemodynamic abnormalities, endothelial and podocyte dysfunction, glomerular basement membrane thickening and mesangial expansion, tubular atrophy, interstitial fibrosis, and a progressive decrease in renal function (increased albuminuria and decreased glomerular filtration rate) leading to end-stage renal disease. [2][3][4][5] There are marked lipid vacuoles present in human and experimental obesity-associated kidney disease; however, the composition and pathways related to their formation is unclear.In a recent study, our group highlighted the appearance of many of these features in high-fat diet (HFD)-induced obesity-related kidney disease model. 6 There was a beneficial effect of the specific central energy sensor AMP-activated protein kinase (AMPK) in regulating the initial inflammatory...