Diabetic nephropathy is an increasingly important cause of morbidity and mortality worldwide. A large body of evidence suggests that dyslipidemia has an important role in the progression of kidney disease in patients with diabetes. Lipids may induce renal injury by stimulating TGF-beta, thereby inducing the production of reactive oxygen species and causing damage to the glomeruli and glomerular glycocalyx. Findings from basic and clinical studies strongly suggest that excess amounts of a variety of lipoproteins and lipids worsens diabetes-associated microvascular and macrovascular disease, increases glomerular injury, increases tubulointerstitial fibrosis, and accelerates the progression of diabetic nephropathy. The increasing prevalence of obesity, type 2 diabetes mellitus, and diabetic nephropathy means that interventions that can interrupt the pathophysiological cascade of events induced by lipoproteins and lipids could enable major life and cost savings. This Review discusses the structural, cellular, and microscopic findings associated with diabetic nephropathy and the influence of lipoproteins, specifically triglyceride-rich lipoproteins (TGRLs), on the development and perpetuation of diabetic nephropathy. Some of the accepted and hypothesized mechanisms of renal injury relating to TGRLs are also described.

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Objective HDL function rather than absolute level may be a more accurate indicator for cardiovascular disease (CVD). Novel methods can measure HDL function using patient samples. The objective of this study is to identify factors that may contribute to HDL dysfunction in chronic, treated HIV-1 infection. Design Retrospective study of HDL function measured in two ways in HIV-1 infected males with low overall CVD risk and healthy males with no known CVD risk matched by race to the HIV-1 infected participants. Methods We examined patient level factors associated with two different measures of HDL dysfunction: reduced antioxidant function (oxidized HDL, HDLox) and reduced HDL-apoA-I exchange (HAE), a measure of HDL remodeling, in the HIV infected and control men. Multivariable-adjusted linear regression analyses were employed adjusting for false discovery rate (FDR), age, race, body mass index (BMI), CD4 count, viremia, CVD risk, smoking, lipids, apoA-I, albumin. Results In multivariate analysis among HIV-1 infected males (n=166) (median age 45 years, CD4 T cell count 505 cells/mm3, 30.1% were viremic), higher BMI, lower apoA-I and lower albumin were among the most notable correlates of higher HDLox and lower HAE (p<0.05). In HIV-1 uninfected participants lower albumin and higher BMI were associated with lower HAE and higher HDLox, respectively (p≤0.05). HDLox was inversely related to HAE in HIV-1 infected individuals (p<0.001). Conclusion Increased HDLox correlates with reduced HAE in chronic HIV-1 infection. Higher BMI, lower apoA-I and albumin were identified as factors associated with HDL dysfunction in chronic HIV-1 infection using two independent methods.

ATP sulfurylase from Penicillium chrysogenum is a homohexameric enzyme that is subject to allosteric inhibition by 3-phosphoadenosine 5-phosphosulfate. In contrast to the wild type enzyme, recombinant ATP sulfurylase lacking the C-terminal allosteric domain was monomeric and noncooperative. All k cat values were decreased (the adenosine 5-phosphosulfate (adenylylsulfate) (APS) synthesis reaction to 17% of the wild type value). Additionally, the Michaelis constants for MgATP and sulfate (or molybdate), the dissociation constant of E⅐APS, and the monovalent oxyanion dissociation constants of dead end E⅐MgATP⅐oxyanion complexes were all increased. APS release (the k 6 step) was rate-limiting in the wild type enzyme. Without the C-terminal domain, the composite k 5 step (isomerization of the central complex and MgPP i release) became rate-limiting. The cumulative results indicate that besides (a) serving as a receptor for the allosteric inhibitor, the C-terminal domain (b) stabilizes the hexameric structure and indirectly, individual subunits. Additionally, (c) the domain interacts with and perfects the catalytic site such that one or more steps following the formation of the binary E⅐MgATP and E⅐SO 4 2Ϫ complexes and preceding the release of MgPP i are optimized. The more negative entropy of activation of the truncated enzyme for APS synthesis is consistent with a role of the C-terminal domain in promoting the effective orientation of MgATP and sulfate at the active site.Most plants and microorganisms can use inorganic sulfate as their sole source of sulfur. Because sulfate is nonreactive at cellular temperatures and pH, the anion must first be "activated" in order to enter the mainstream of metabolism. Activation proceeds in two steps. These are catalyzed, in order, by the enzymes ATP sulfurylase (MgATP:sulfate adenylyltransferase; EC 2.7.7.4) and adenosine 5Ј-phosphosulfate (APS) 1 kinase (MgATP:APS 3Ј-phosphotransferase; EC 2.7.1.25). The sequential reactions produce the sulfonucleotides APS and 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS). ATP sulfurylase from the filamentous fungus, Penicillium chrysogenum, is a homooligomer composed of six 63.7-kDa subunits (573 residues). PAPS, the APS kinase product, is an allosteric inhibitor (1, 2). This inhibition may be part of a sequential feedback process, considering that PAPS is a major branch point metabolite in filamentous fungi but not in other organisms. (PAPS enters into the cysteine biosynthetic pathway and is also used by filamentous fungi for the formation of choline-O-sulfate, a sulfur storage compound and/or osmoprotectant (3-6)).P. chrysogenum ATP sulfurylase is organized as a dimer of triads (7-9). Each subunit is composed of three structurally distinct globular regions. Residues 1-170 compose a distinct N-terminal domain. Residues 171-395 compose the central catalytic domain. Several residues that have been shown to be essential for activity (10, 11) are located in this domain. Residues 331-389 form a small subdomain, called Domain III in the yeast stru...

Dyslipidemia is implicated as a risk factor for the development of atherosclerosis. Specifically triglyceride-rich lipoproteins (TGRL) and their lipolysis products are shown to be pro-inflammatory and pro-apoptosis in both in vivo and in vitro studies with endothelium. However the role of TGRL in the progression of kidney diseases is not clear. Epidemiology studies demonstrated a correlation between renal disease and blood lipids. Recent evidence suggests that the mechanism may involve cellular uptake of lipid and de novo lipogenesis. Further studies are needed to establish the relevance of these mechanistic studies in human pathophysiology.