Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids and its modification by Stearoyl-CoA desaturases and cyclic AMP

Podocyte apoptosis is a hallmark in the development and progression of diabetic nephropathy (DN). Several factors of the diabetic milieu are known to induce podocyte apoptosis. Currently, the role of free fatty acids (FFAs) for podocytopathy and podocyte cell death is unknown, although FFAs are considered to be crucially involved in the development of diabetes mellitus type II. It is well known that FFAs are toxic to several cell types including pancreatic § cells and they may contribute to the development of insulin resistance. The aims of this study were to elucidate the role of the saturated palmitic acid and the monounsaturated palmitoleic and oleic acid on podocyte cell death and endoplasmic reticulum (ER)-stress, to investigate more specifically the impact of ER-stress on podocyte survival as well as to elaborate strategies to protect podocytes from lipotoxicity. The present study uncovered that palmitic acid induces podocyte apoptosis and necrosis and leads to ER-stress as reflected by induction of the unfolded protein response (UPR), i.e. upregulation of the ER chaperone immunoglobulin heavy chain binding protein (BiP), X-box protein 1 (XBP-1) mRNA splicing, and a strong upregulation of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Gene silencing experiments of CHOP support a crucial involvment of CHOP and ER-stress in mediating the proapoptotic effect of palmitic acid in podocytes. Contrariwise, monounsaturated FFAs (MUFAs) such as palmitoleic and oleic acid prevent palmitic acid-induced podocyte death and attenuate ER-stress. This study further revealed that the liver X receptor (LXR) agonist TO901317 (TO) ameliorates survival of palmitic acid-treated podocytes. Mechanistically, this beneficial effect can be explained mainly by the induction of stearoyl-CoA desaturase (SCD-) 1 and 2 as shown by gene silencing experiments and further supported from overexpression studies of SCD-1. Moreover, palmitic acid tracing experiments revealed a higher incorporation of palmitic acid into the triglyceride (TG) fraction in podocytes treated with TO or oleic acid, which is at least compatible with a benefit of increased fatty acid storage, by TO, i.e. SCDs, and MUFAs, respectively. In addition, this study provides some preliminary data that adenylate cyclases (AC) may be an interesting target to protect podocytes from ER-stress in general and in particular from palmitic acid-induced podocytopathy and cell death. Experiments with forskolin, a specific AC agonist, and cyclic AMP (cAMP) analogons protect from palmitic acid-induced podocyte lipotoxicity. The effect cannot be explained by an involvment of PKA-CREB signaling as overexpression of a dominant negative CREB mutant could not abrogate the protective effect of forskolin. Furthermore, the beneficial impact of forskolin is not influencing the intrinisic (mitochondrial) apoptotic pathway. However, in addition to the protection from palmitic acid-induced cell death, forskolin is suppressing podocyte death caused by other independent ER-stressors such as tunicamycin and thapsigargin. These findings suggest a direct role of forskolin and increased cAMP levels for a protection from ER-stress in podocytes. In summary, this study unveiled antagonistic effects of palmitic acid versus monounsaturated FFAs for podocyte survival, ER-stress and the UPR. They support an important role of CHOP in the regulation of podocyte death by FFAs. Similarly to exogenous MUFAs, induction of SCDs partially protects podocytes from palmitic acid-induced ER-stress and podocyte death. The protective effect of MUFAs may be related to increased incorporation of palmitic acid into TGs. Additional, preliminary data indicate that AC agonists such as forskolin may be interesting compounds to protect podocytes from ER-stress and from the toxic effects of FFAs. The results of this study offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward MUFAs, or tissue- (podocyte-) specific stimulation or overexpression of SCDs can delay the progression of DN. Similarly, the results of this study should encourage more studies to evaluate the therapeutic potential of AC agonists or phosphodiesterase inhibitors for the prevention and treatment of DN

Leading off-diagonal approximation for the spectral form factor for uniformly hyperbolic systems

We consider the semiclassical approximation to the spectral form factor K(tau) for two-dimensional uniformly hyperbolic systems, and derive the first off-diagonal correction for small tau. The result agrees with the tau^2-term of the form factor for the GOE random matrix ensemble.Comment: 8 pages, 3 figure

[Review of] Jack D. Forbes. Native Americans and Nixon: Presidential Politics and Minority Self-Determination 1969-1972

In Native Americans and Nixon, Jack D. Forbes, author of several monographs on the Indian in America\u27s past, has undertaken an important subject, one also difficult because essential sources are lacking. Forbes therefore employs a number of hedges such as we can only guess (116) in his conjecture about the motives and actions of the Nixon administration relative to Indian Americans. In a foreword taking twenty-three of the 124 pages of text, Roxanne Dunbar Ortiz of California State University, Hayward, sets the theme of neocolonialism. Explaining the background of post-World War II techniques of colonial control, she states that Hundreds of thousands of democratic groups were executed or imprisoned by United States forces directly or through military training and aid to puppet regimes (7). Readers receptive to this statement will have little difficulty in speculating with these writers that Nixon\u27s words were hollow when he stated in 1970 that We must assure the Indian that he can assume control of his own life without being separated involuntarily from the tribal group (5)

Probability of noise- and rate-induced tipping

We propose an approximation for the probability of tipping when the speed of parameter change and additive white noise interact to cause tipping. Our approximation is valid for small to moderate drift speeds and helps to estimate the probability of false positives and false negatives in early-warning indicators in the case of rate- and noise-induced tipping. We illustrate our approximation on a prototypical model for rate-induced tipping with additive noise using Monte-Carlo simulations. The formula can be extended to close encounters of rate-induced tipping and is otherwise applicable to other forms of tipping. We also provide an asymptotic formula for the critical ramp speed of the parameter in the absence of noise for a general class of systems undergoing rate-induced tipping.Comment: 14 pages, 9 figures https://link.aps.org/doi/10.1103/PhysRevE.95.05220

The semiclassical relation between open trajectories and periodic orbits for the Wigner time delay

The Wigner time delay of a classically chaotic quantum system can be expressed semiclassically either in terms of pairs of scattering trajectories that enter and leave the system or in terms of the periodic orbits trapped inside the system. We show how these two pictures are related on the semiclassical level. We start from the semiclassical formula with the scattering trajectories and derive from it all terms in the periodic orbit formula for the time delay. The main ingredient in this calculation is a new type of correlation between scattering trajectories which is due to trajectories that approach the trapped periodic orbits closely. The equivalence between the two pictures is also demonstrated by considering correlation functions of the time delay. A corresponding calculation for the conductance gives no periodic orbit contributions in leading order.Comment: 21 pages, 5 figure