Regulation of the Homeostatic Unfolded Protein Response in Diabetic Nephropathy

A growing body of scientific evidence indicates that protein homeostasis, also designated as proteostasis, is causatively linked to chronic diabetic nephropathy (DN). Experimental studies have demonstrated that the insulin signaling in podocytes maintain the homeostatic unfolded protein response (UPR). Insulin signaling via the insulin receptor non-canonically activates the spliced X-box binding protein-1 (sXBP1), a highly conserved endoplasmic reticulum (ER) transcription factor, which regulates the expression of genes that control proteostasis. Defective insulin signaling in mouse models of diabetes or the genetic disruption of the insulin signaling pathway in podocytes propagates hyperglycemia induced maladaptive UPR and DN. Insulin resistance in podocytes specifically promotes activating transcription factor 6 (ATF6) dependent pathogenic UPR. Akin to insulin, recent studies have identified that the cytoprotective effect of anticoagulant serine protease-activated protein C (aPC) in DN is mediated by sXBP1. In mouse models of DN, treatment with chemical chaperones that improve protein folding provides an additional benefit on top of currently used ACE inhibitors. Understanding the molecular mechanisms that transmute renal cell specific adaptive responses and that deteriorate renal function in diabetes will enable researchers to develop new therapeutic regimens for DN. Within this review, we focus on the current understanding of homeostatic mechanisms by which UPR is regulated in DN

Regulation of the homeostatic unfolded protein response in diabetic nephropathy

A growing body of scientific evidence indicates that protein homeostasis, also designated as proteostasis, is causatively linked to chronic diabetic nephropathy (DN). Experimental studies have demonstrated that the insulin signaling in podocytes maintain the homeostatic unfolded protein response (UPR). Insulin signaling via the insulin receptor non-canonically activates the spliced X-box binding protein-1 (sXBP1), a highly conserved endoplasmic reticulum (ER) transcription factor, which regulates the expression of genes that control proteostasis. Defective insulin signaling in mouse models of diabetes or the genetic disruption of the insulin signaling pathway in podocytes propagates hyperglycemia induced maladaptive UPR and DN. Insulin resistance in podocytes specifically promotes activating transcription factor 6 (ATF6) dependent pathogenic UPR. Akin to insulin, recent studies have identified that the cytoprotective effect of anticoagulant serine protease-activated protein C (aPC) in DN is mediated by sXBP1. In mouse models of DN, treatment with chemical chaperones that improve protein folding provides an additional benefit on top of currently used ACE inhibitors. Understanding the molecular mechanisms that transmute renal cell specific adaptive responses and that deteriorate renal function in diabetes will enable researchers to develop new therapeutic regimens for DN. Within this review, we focus on the current understanding of homeostatic mechanisms by which UPR is regulated in DN

Negative interactions and feedback regulations are required for transient cellular response.

Signal transduction is a process required to conduct information from a receptor to the nucleus. This process is vital for the control of cellular function and fate. The dynamics of signaling activation and inhibition determine processes such as apoptosis, proliferation, and differentiation. Thus, it is important to understand the factors modulating transient and sustained response. To address this question, by applying mathematical approach we have studied the factors which can alter the activation nature of downstream signaling molecules. The factors which we have investigated are loops (feed forward and feedback loops), cross-talk of signal transduction pathways, and the change in the concentration of the signaling molecules. Based on our results we conclude that among these factors feedback loop and the cross-talks which directly inhibit the target protein dominantly controls the transient cellular response

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

WOS: 000411319700011PubMed ID: 28687614Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling impair function of podocytes and ultimately cause dysfunction of the glomerular filtration barrier and diabetic kidney disease (DKD). We here show that insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signaling pathway to maintain endoplasmic reticulum(ER) homeostasis. Analogous to insulin, physiological levels of aPCmaintain ER proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER response, whereas genetic or pharmacological restoration of aPC maintains ER proteostasis in DKD models. Importantly, in mice with podocyte-specific deficiency of insulin receptor (INSR), aPC selectively restores the activity of the cytoprotective ER-transcription factor sXBP1 by temporally targeting INSR downstream signaling intermediates, the regulatory subunits of PI3Kinase, p85a and p85b. Genomewide mapping of condition-specific XBP1-transcriptional regulatory patterns confirmed that concordant unfolded protein response target genes are involved inmaintenance of ER proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to reconfigure ER signaling and restore proteostasis. These results identify ER reprogramming as a novel hormonelike function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.Deutsche Forschungsgemeinschaft [IS 67/5-2, IS-67/8-1, IS 67/11-1, SFB 845 B26N, SFB 854 Z01, TH 1789/1-1, WA 3663/2-1, CH279/5-1, SFB 1118]; Stiftung Pathobiochemie und Molekulare Diagnostik; European Research Council (DEMETINL); Federal Ministry of Education and Research [BMBF 01EO1503]; Alexander von Humboldt Foundation; DAAD scholarshipsThis work was supported by grants from the Deutsche Forschungsgemeinschaft (IS 67/5-2, IS-67/8-1, IS 67/11-1, and SFB 845 B26N) (B.I.) and SFB 854 Z01 (A.J.M.), TH 1789/1-1 (T.M.), WA 3663/2-1 (H.W.), CH279/5-1 (T.C.), and SFB 1118 (P.P.N.), the "Stiftung Pathobiochemie und Molekulare Diagnostik" (B.I. and T.M.), the European Research Council (DEMETINL) (T.C.), Federal Ministry of Education and Research (BMBF 01EO1503), Alexander von Humboldt Foundation (W.R.), and DAAD scholarships (M.M.A.-D. and A.E.)

Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cells via aberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD

An Exosite-Specific ssDNA Aptamer Inhibits the Anticoagulant Functions of Activated Protein C and Enhances Inhibition by Protein C Inhibitor

SummaryActivated protein C (APC) is a serine protease with anticoagulant, anti-inflammatory, and cytoprotective properties. Using recombinant APC, we identified a class of single-stranded DNA aptamers (HS02) that selectively bind to APC with high affinity. Interaction of HS02 with APC modulates the protease activity in a way such that the anticoagulant functions of APC are inhibited and its reactivity toward the protein C inhibitor is augmented in a glysoaminoglycan-like fashion, whereas APC's antiapoptotic and cytoprotective functions remain unaffected. Based on these data, the binding site of HS02 was localized to the basic exosite of APC. These characteristics render the exosite-specific aptamers a promising tool for the development of APC assays and a potential therapeutic agent applicable for the selective control of APC's anticoagulant activity

Deletion of endothelial leptin receptors in mice promotes diet-induced obesity

Abstract Obesity promotes endothelial dysfunction. Endothelial cells not only respond, but possibly actively promote the development of obesity and metabolic dysfunction. Our aim was to characterize the role of endothelial leptin receptors (LepR) for endothelial and whole body metabolism and diet-induced obesity. Mice with tamoxifen-inducible, Tie2.Cre-ERT2-mediated deletion of LepR in endothelial cells (End.LepR knockout, KO) were fed high-fat diet (HFD) for 16 weeks. Body weight gain, serum leptin levels, visceral adiposity and adipose tissue inflammation were more pronounced in obese End.LepR-KO mice, whereas fasting serum glucose and insulin levels or the extent of hepatic steatosis did not differ. Reduced brain endothelial transcytosis of exogenous leptin, increased food intake and total energy balance were observed in End.LepR-KO mice and accompanied by brain perivascular macrophage accumulation, whereas physical activity, energy expenditure and respiratory exchange rates did not differ. Metabolic flux analysis revealed no changes in the bioenergetic profile of endothelial cells from brain or visceral adipose tissue, but higher glycolysis and mitochondrial respiration rates in those isolated from lungs. Our findings support a role for endothelial LepRs in the transport of leptin into the brain and neuronal control of food intake, and also suggest organ-specific changes in endothelial cell, but not whole-body metabolism

Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy

Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.Funding Agencies|Deutsche Forschungsgemeinschaft [IS 67/2-4, TH 1789/1-1, BI 1281/3-1]; EFSD (European Foundation for the Study of Diabetes); DDS (Deutsche Diabetes Stiftung); Hopp Stiftung; Stiftung fur Pathobiochemie und Molekulare Diagnostik; ERC StG; BioSysNet Research group</p