Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy.
Journal of the American Society of Nephrology 27(8):2270 (2016)
Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8)...
The emerging role of coagulation proteases in kidney disease.
Nature Reviews: Nephrology 12(2):94 (2016)
A role of coagulation proteases in kidney disease beyond their function in normal haemostasis and thrombosis has long been suspected, and studies performed in the past 15 years have provided novel insights into the mechanisms involved. The expression of protease-activated receptors (PARs) in ren...
Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination.
Journal of the American Society of Nephrology 26(11):2789 (2015)
Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undef...
Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.
Kidney International 87(1):74 (2015)
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 neph...
Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy.
Nature Communications 6:6496 (2015)
Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding pr...
Negative interactions and feedback regulations are required for transient cellular response.
Scientific reports 4:3718 (2014)
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. Thu...
Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.
PNAS 110(2):648 (2013)
The coagulation protease activated protein C (aPC) confers cytoprotective effects in various in vitro and in vivo disease models, including diabetic nephropathy. The nephroprotective effect may be related to antioxidant effects of aPC. However, the mechanism through which aPC may convey these an...
The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition.
Thrombosis and Haemostasis 108(6):1141 (2012)
Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM's lectin like domain dampens complement activation, whi...
Human RAGE antibody protects against AGE-mediated podocyte dysfunction.
Nephrology Dialysis Transplantation 27(8):3129 (2012)
Residual renal function (RRF) contributes to better patient survival in peritoneal dialysis (PD). It is known that glucose degradation products (GDP) and advanced glycation end-products (AGE) resorbed from the peritoneal cavity do not only cause local peritoneal toxicity but also systemic damage...
Nuclear factor erythroid-derived 2 (Nfe2) regulates JunD DNA-binding activity via acetylation: a novel mechanism regulating trophoblast differentiation.
Journal of Biological Chemistry 287(8):5400 (2012)
We recently demonstrated that the bZip transcription factor nuclear factor erythroid-derived 2 (Nfe2) represses protein acetylation and expression of the transcription factor glial cell missing 1 (Gcm1) in trophoblast cells, preventing excess syncytiotrophoblast formation and permitting normal p...
Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes.
Blood 119(3):874 (2012)
The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a pro...
Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy.
Blood 117(19):5231 (2011)
Whereas it is generally perceived to be harmful, enhanced coagulation activation can also convey salutary effects. The high prevalence of the prothrombotic factor V Leiden (FVL) mutation in whites has been attributed to a positive selection pressure (eg, resulting from reduced blood loss or impr...
Hypercoagulability inhibits monocyte transendothelial migration through protease-activated receptor-1-, phospholipase-Cbeta-, phosphoinositide 3-kinase-, and nitric oxide-dependent signaling in monocytes and promotes plaque stability.
Circulation 120(9):774 (2009)
Clinical studies failed to provide clear evidence for a proatherogenic role of hypercoagulability. This is in contrast to the well-established detrimental role of hypercoagulability and thrombin during acute atherosclerotic complications. These seemingly opposing data suggest that hypercoagulabi...
An exosite-specific ssDNA aptamer inhibits the anticoagulant functions of activated protein C and enhances inhibition by protein C inhibitor.
Chemistry & Biology 16(4):442 (2009)
Activated 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 pro...
Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.
Nature Medicine 13(11):1349 (2007)
Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally l...