The Role of Hypoxia on the Trimethylation of H3K27 in Podocytes.

Epigenetic alterations contribute to the pathogenesis of chronic diseases such as diabetes mellitus. Previous studies of our group showed that diabetic conditions reduce the trimethylation of H3K27 in podocytes in a NIPP1- (nuclear inhibitor of protein phosphatase 1) and EZH2- (enhancer of zeste homolog 2) dependent manner. It has been previously reported that in differentiated podocytes, hypoxia decreases the expression of slit diaphragm proteins and promotes foot process effacement, thereby contributing to the progression of renal disease.

Targeted Disruption of the MORG1 Gene in Mice Causes Embryonic Resorption in Early Phase of Development.

The mitogen-activated protein kinase organizer 1 (MORG1) is a scaffold molecule for the ERK signaling pathway, but also binds to prolyl-hydroxylase 3 and modulates HIFα expression. To obtain further insight into the role of MORG1, knockout-mice were generated by homologous recombination. While Morg1+/- mice developed normally without any apparent phenotype, there were no live-born Morg1-/- knockout offspring, indicating embryonic lethality.

Sex-Related Aspects in Diabetic Kidney Disease-An Update.

Differences between the sexes exist in many diseases, and in most cases, being a specific sex is considered a risk factor in the development and/or progression. This is not quite so clear in diabetic kidney disease (DKD), the development and severity of which depends on many general factors, such as the duration of diabetes mellitus, glycemic control, and biological risk factors. Similarly, sex-specific factors, such as puberty or andro-/menopause, also determine the microvascular complications in both the male and female sex.

RAGE is a critical factor of sex-based differences in age-induced kidney damage.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules with potential pathophysiological effects on the kidneys. Fibrosis together with the accumulation of AGEs has been investigated for its contribution to age-related decline in renal function. AGEs mediate their effects in large parts through their interactions with the receptor for AGEs (RAGE).

MORG1-A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes.

Renal fatty acid (FA) metabolism is severely altered in type 1 and 2 diabetes mellitus (T1DM and T2DM). Increasing evidence suggests that altered lipid metabolism is linked to tubulointerstitial fibrosis (TIF). Our previous work has demonstrated that mice with reduced MORG1 expression, a scaffold protein in HIF and ERK signaling, are protected against TIF in the db/db mouse model.

Sex Differences in Diabetes- and TGF-β1-Induced Renal Damage.

While females are less affected by non-diabetic kidney diseases compared to males, available data on sex differences in diabetic nephropathy (DN) are controversial. Although there is evidence for an imbalance of sex hormones in diabetes and hormone-dependent mechanisms in transforming growth factor β1 (TGF-β1) signaling, causes and consequences are still incompletely understood. Here we investigated the influence of sex hormones and sex-specific gene signatures in diabetes- and TGF-β1-induced renal damage using various complementary approaches (a diabetes mouse model, ex vivo experiments on murine renal tissue, and experiments with a proximal tubular cell line TKPTS).

MKP2 suppresses TGF-β1-induced epithelial-to-mesenchymal transition through JNK inhibition.

Interstitial fibrosis is a typical feature of end-stage renal diseases, regardless of the initial cause of kidney injury. Epithelial-to-mesenchymal transition (EMT) is a mechanism that is thought to play a role in generating the interstitial matrix-producing myofibroblasts and is prominently induced by the transforming growth factor-β 1 (TGF-β1). TGF-β1 signals through a variety of Smad and non-Smad signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways.

CERA Attenuates Kidney Fibrogenesis in the db/db Mouse by Influencing the Renal Myofibroblast Generation.

Tubulointerstitial fibrosis (TIF) is a pivotal pathophysiological process in patients with diabetic nephropathy (DN). Multiple profibrotic factors and cell types, including transforming growth factor beta 1 (TGF-β1) and interstitial myofibroblasts, respectively, are responsible for the accumulation of extracellular matrix in the kidney. Matrix-producing myofibroblasts can originate from different sources and different mechanisms are involved in the activation process of the myofibroblasts in the fibrotic kidney.

FSP1-specific SMAD2 knockout in renal tubular, endothelial, and interstitial cells reduces fibrosis and epithelial-to-mesenchymal transition in murine STZ-induced diabetic nephropathy.

Extracellular matrix deposition during tubulointerstitial fibrosis (TIF), a central pathological process in patients with diabetic nephropathy (DN), is driven by locally activated, disease-relevant myofibroblasts. Myofibroblasts can arise from various cellular sources, e.g.

Heterozygosity of mitogen-activated protein kinase organizer 1 ameliorates diabetic nephropathy and suppresses epithelial-to-mesenchymal transition-like changes in db/db mice.

Background: Progressive diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis that is caused by accumulation of extracellular matrix. Induced by several factors, matrix-producing myofibroblasts may to some extent originate from tubular cells by epithelial-to-mesenchymal transition (EMT). Although previous data document that activation of hypoxia-inducible factor (HIF) signalling can be renoprotective in acute kidney disease, this issue remains controversial in chronic kidney injury.

Changeover from signalling to energy-provisioning lipids during transition from colostrum to mature milk in the giant panda (Ailuropoda melanoleuca).

Among the large placental mammals, ursids give birth to the most altricial neonates with the lowest neonatal:maternal body mass ratios. This is particularly exemplified by giant pandas. To examine whether there is compensation for the provision of developmentally important nutrients that other species groups may provide in utero, we examined changes in the lipids of colostrum and milk with time after birth in giant pandas.

Changes in the Milk Metabolome of the Giant Panda (Ailuropoda melanoleuca) with Time after Birth--Three Phases in Early Lactation and Progressive Individual Differences.

Ursids (bears) in general, and giant pandas in particular, are highly altricial at birth. The components of bear milks and their changes with time may be uniquely adapted to nourish relatively immature neonates, protect them from pathogens, and support the maturation of neonatal digestive physiology. Serial milk samples collected from three giant pandas in early lactation were subjected to untargeted metabolite profiling and multivariate analysis.

Prolonged transition time between colostrum and mature milk in a bear, the giant panda, Ailuropoda melanoleuca.

Bears produce the most altricial neonates of any placental mammal. We hypothesized that the transition from colostrum to mature milk in bears reflects a temporal and biochemical adaptation for altricial development and immune protection. Comparison of bear milks with milks of other eutherians yielded distinctive protein profiles.

Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy: Fact or Fiction?

The pathophysiology of diabetic nephropathy (DN), one of the most serious complications in diabetic patients and the leading cause of end-stage renal disease worldwide, is complex and not fully elucidated. A typical hallmark of DN is the excessive deposition of extracellular matrix (ECM) proteins in the glomerulus and in the renal tubulointerstitium, eventually leading to glomerulosclerosis and interstitial fibrosis. Although it is obvious that myofibroblasts play a major role in the synthesis and secretion of ECM, the origin of myofibroblasts in DN remains the subject of controversial debates.

The role of hypoxia and Morg1 in renal injury.

Background: Renal hypoxia is known to play an important role in the pathophysiology of acute renal injury as well as in chronic kidney diseases. The mediators of hypoxia are the transcription factors HIF (hypoxia-inducible factors), that are highly regulated. Under normoxic conditions constitutively expressed HIF-α subunits are hydroxylated by prolyl hydroxylases (PHD1, PHD2, and PHD3) and subsequently degraded by proteasomes.

Morg1 heterozygous deficiency ameliorates hypoxia-induced acute renal injury.

Acute kidney injury is a common complication of critically ill patients and may occur as a result of various factors and coexisting previous illnesses. Some pathophysiological responses seen in critical illness can be similar to the human physiological response to extreme environmental challenges, such as hypoxia from reduced oxygen availability at high altitudes (systemic hypoxia). Due to oxygen deficiency, mammalian cells activate the transcriptional factor hypoxia-inducible factor (HIF); its degradation is regulated by prolyl hydroxylase 3 (PHD3) in interaction with the scaffold protein MAPK organizer 1 (Morg1).

Transforming growth factor-β and the progression of renal disease.

Transforming growth factor-β (TGF-β) is a profibrotic cytokine found in chronic renal diseases, which initiates and modulates a variety of pathophysiological processes. It is synthesized by many renal cell types and exerts its biological functions through a variety of signalling pathways, including the Smad and MAPK pathways. In renal diseases, TGF-β is upregulated and induces renal cells to produce extracellular matrix proteins leading to glomerulosclerosis as well as tubulointerstitial fibrosis.

Erythropoietin ameliorates podocyte injury in advanced diabetic nephropathy in the db/db mouse.

Podocyte damage and accumulation of advanced glycation end products (AGEs) are characteristics of diabetic nephropathy (DN). The pathophysiology of AGE-challenged podocytes, such as hypertrophy, apoptosis, and reduced cell migration, is closely related to the induction of the cell cycle inhibitor p27(Kip1) and to the inhibition of neuropilin 1 (NRP1). We have previously demonstrated that treatment with erythropoietin is associated with protective effects for podocytes in vitro.

Collagen VIII influences epithelial phenotypic changes in experimental diabetic nephropathy.

Epithelial-to-mesenchymal transition (EMT) is an important mechanism of renal tubulo-interstitial fibrosis in diabetic nephropathy (DN). Inducers of EMT, among others, are transforming growth factor-β(1) (TGF-β(1)) as well as extracellular collagens. In renal cells of diabetic mice and in kidneys of patients with DN, the expression of collagen VIII (gene: Col8α1/α2) is enhanced and characteristic features of DN in streptozotocin (STZ)-induced diabetic Col8α1/α2 knockout-(KO) mice are attenuated compared with diabetic wild-type mice.

Type VIII collagen modulates TGF-β1-induced proliferation of mesangial cells.

Mesangial cells in diabetic mice and human kidneys with diabetic nephropathy exhibit increased type VIII collagen, a nonfibrillar protein that exists as a heterodimer composed of α1(VIII) and α2(VIII), encoded by Col8a1 and Col8a2, respectively. Because TGF-β1 promotes the development of diabetic glomerulosclerosis, we studied whether type VIII collagen modulates the effects of TGF-β1 in mesangial cells. We obtained primary cultures of mesangial cells from wild-type, doubly heterozygous (Col8a1(+/-)/Col8a2(+/-)), and double-knockout (Col8a1(-/-)/Col8a2(-/-)) mice.

Fibrosis in endstage human heart failure: severe changes in collagen metabolism and MMP/TIMP profiles.

Objectives: We studied fibrosis, collagen metabolism, MMPs/TIMPs and cytokine expression in various forms of human heart failure (HF) by quantitative immunofluorescent microscopy, Western blot, zymography, RT-PCR and in situ hybridization. In explanted human hearts with HF due to either dilated (DCM, n=6) or ischemic (ICM-BZ-borderzone, ICM-RZ-remote zone, n=7) or inflammatory (myocarditis, MYO, n=6) cardiomyopathy and 8 controls MMP2, 8, 9, 19, and TIMP1, 2, 3, 4 as well as procollagens I and III (PINP, PIIINP), mature collagen III (IIINTP) and the cross-linked collagen I degradation product (ICTP) were measured.

Results: In comparison with controls, MMPs and TIMPs were significantly upregulated ranging (from highest to lowest) from ICM-BZ, DCM, ICM-RZ, MYO for all MMPs with the exception of MMP9 (highest in DCM), and for TIMPs from ICM-BZ, ICM-RZ, DCM and MYO.

Morg1 heterozygous mice are protected from acute renal ischemia-reperfusion injury.

Renal ischemia and reperfusion injury leads to acute renal failure when proinflammatory and apoptotic processes in the kidney are activated. The increase in hypoxia-inducible transcription factor-alpha (HIF-alpha), an important transcription factor for several genes, can attenuate ischemic renal injury. We recently identified a novel WD-repeat protein designated Morg1 (MAPK organizer 1) that interacts with prolyl hydroxylase 3 (PHD3), an important enzyme involved in the regulation of HIF-1alpha and HIF-2alpha expression.

Lack of type VIII collagen in mice ameliorates diabetic nephropathy.

Objective: Key features of diabetic nephropathy include the accumulation of extracellular matrix proteins. In recent studies, increased expression of type VIII collagen in the glomeruli and tubulointerstitium of diabetic kidneys has been noted. The objectives of this study were to assess whether type VIII collagen affects the development of diabetic nephropathy and to determine type VIII collagen-dependent pathways in diabetic nephropathy in the mouse model of streptozotocin (STZ)-induced diabetes.