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. A number of studies have focused on epithelial-to-mesenchymal transition (EMT) as one source of matrix-generating fibroblasts in the diseased kidney. EMT is characterized by the acquisition of mesenchymal properties by epithelial cells, preferentially proximal tubular cells and podocytes. In this review we comprehensively review the literature and discuss arguments both for and against a function of EMT in renal fibrosis in DN. While the precise extent of the contribution to nephrotic fibrosis is certainly arduous to quantify, the picture that emerges from this extensive body of literature suggests EMT as a major source of myofibroblasts in DN.
Angiotensin II (AngII) is an important mediator in renal injury. Accumulating evidence suggests that AngII stimulates intracellular formation of reactive oxygen species (ROS) such as the superoxide ...anion and hydrogen peroxide. AngII activates several subunits of the membrane-bound multicomponent NAD(P)H oxidase and also increases ROS formation in the mitochondria. Some of these effects may be induced by aldosterone and not directly by AngII. The superoxide anion and hydrogen peroxide influence other downstream signaling pathways, such as transcription factors, tyrosine kinases/phosphatases, ion channels, and mitogen-activated protein kinases. Through these signaling pathways, ROS have distinct functional effects on renal cells. They are transducers of cell growth, apoptosis, and cell migration and affect expression of inflammatory and extracellular matrix genes. For example, AngII-mediated expression of p27(Kip1), a cell-cycle regulatory protein, and induction of tubular hypertrophy depend on the generation of ROS. The effects of ROS generated within different renal cells ultimately depend on the locally generated concentrations and the balance of pro- and antioxidant pathways. Although the concept that AngII mediates oxidative stress in the kidney has been validated in experimental models, the exact role is still incompletely understood in human renal diseases.
Obesity is an independent risk factor for the development and progression of chronic kidney disease and one of the emerging reasons for end-stage renal disease owing to its dramatic increase ...worldwide. Among the potential underlying pathophysiologic mechanisms, activation of the renin-angiotensin-aldosterone-system (RAAS) plays a central role. Increased angiotensin II (AngII) levels also are central in hypertension, dyslipidemia, and insulin resistance, which, taken together with obesity, represent the metabolic syndrome. Increased AngII levels contribute to hyperfiltration, glomerulomegaly, and subsequent focal glomerulosclerosis by altering renal hemodynamics via afferent arteriolar dilation, together with efferent renal arteriolar vasoconstriction as well as by its endocrine and paracrine properties linking the intrarenal and the systemic RAAS, adipose tissue dysfunction, as well as insulin resistance and hypertension. The imbalance between increased AngII levels and the angiotensin converting enzyme 2/Ang (1-7)/Mas receptor axis additionally contributes to renal injury in obesity and its concomitant metabolic disturbances. As shown in several large trials and experimental studies, treatment of obesity by weight loss is associated with an improvement of kidney disease because it also is beneficial in dyslipidemia, hypertension, and diabetes. The most promising data have been seen by RAAS blockade, pointing to the central position of RAAS within obesity, kidney disease, and the metabolic syndrome.
MAPK-organizer 1 (MORG1) is a molecular scaffold for prolyl-hydroxylase-3 containing a domain (PHD3) protein linking MORG1 to mechanisms of adaptation in hypoxic conditions. In this paper, we report ...the cloning of the promoter region of the murine and human
gene. Among other transcriptional factors binding sites, we identified that both (mouse and human) promoter regions contained several putative hypoxia-inducible factor binding motifs. Analyses of the human
promoter by reporter assays revealed that hypoxia and pharmacological inhibitors of prolyl-hydroxylases under in vitro conditions in HEK 293 cells differentially regulate the
promoter reporter activity. The exposure of the cells to 10% hypoxia showed inhibition of MORG1 promotor activity at 6 and 12 h, but stimulation after 24 h while treated with prolyl-hydroxylase inhibitors led to a time-independent MORG1 promoter activation. Mutational analyses of the individual HIF binding sites on human
promoter suggest that the binding sites work in a complex corporation because single mutations were not sufficient to abolish completely the
reporter activation by PHD inhibitors. Our data provide the first evidence that not only MORG1 regulate HIF stabilization through a PHD complex, but also that, vice versa, HIFs control MORG1 expression directly or indirectly by a complex regulatory mechanism.
The gradual loss of kidney function due to increasing age is accompanied by structural changes such as fibrosis of the tissue. The underlying molecular mechanisms are complex, but not yet fully ...understood. Non-fibrillar collagen type VIII (COL8) could be a potential factor in the fibrosis processes of the aging kidney. A pathophysiological significance of COL8 has already been demonstrated in the context of diabetic kidney disease, with studies showing that it directly influences both the development and progression of renal fibrosis occurring. The aim of this study was to investigate whether COL8 impacts age-related micro-anatomical and functional changes in a mouse model. The kidneys of wild-type (
-wt) and COL8-knockout (
-ko) mice of different age and sex were characterized with regard to the expression of molecular fibrosis markers, the development of nephrosclerosis and renal function. The age-dependent regulation of COL8 mRNA expression in the wild-type revealed sex-dependent effects that were not observed with collagen IV (COL4). Histochemical staining and protein analysis of profibrotic cytokines TGF-β1 (transforming growth factor) and CTGF (connective tissue growth factor) in mouse kidneys showed significant age effects as well as interactions of the factors age, sex and
genotype. There were also significant age and
genotype effects in the renal function data analyzed by urinary cystatin C. In summary, the present study shows, for the first time, that COL8 is regulated in an age- and sex-dependent manner in the mouse kidney and that the expression of COL8 influences the severity of age-induced renal fibrosis and function.
Microalbuminuria is the earliest detectable clinical abnormality in diabetic glomerulopathy. On a molecular level, metabolic pathways activated by hyperglycemia, glycated proteins, hemodynamic ...factors, and oxidative stress are key players in the genesis of diabetic kidney disease. A variety of growth factors and cytokines are then induced through complex signal transduction pathways. Transforming growth factor-beta 1 (TGF-beta1) has emerged as an important downstream mediator for the development of renal hypertrophy and the accumulation of mesangial extracellular matrix components, but there is limited evidence to support its role in the development of albuminuria. The loss of proteoglycans in the glomerular basement membrane (GBM) has been recently questioned as causative of the albuminuria, and current research has focused on the podocyte as a central target for the effects of the metabolic milieu in the development and progression of diabetic albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is increased in diabetic kidney disease, is perhaps a major mediator of the increased protein filtration. Decreased podocyte number and/or density as a result of apoptosis or detachment, GBM thickening with altered matrix composition, and a reduction in nephrin protein in the slit diaphragm with podocyte foot process effacement, all comprise the principal features of diabetic podocytopathy that clinically manifests as albuminuria and proteinuria. Many of these events are mediated by angiotensin II whose local concentration is stimulated by high glucose, mechanical stretch, and proteinuria itself. Angiotensin II in turn stimulates podocyte-derived VEGF, suppresses nephrin expression, and induces TGF-beta1 leading to podocyte apoptosis and fostering the development of glomerulosclerosis. Proteinuria can then induce in tubular cells a genetic program leading to tubulointerstitial inflammation, fibrosis and tubular atrophy. Besides direct effects of albuminuria on tubular cells, pathophysiological changes in the ultrafiltration barrier lead to an increased tubular filtration of various growth factors (TGF-beta1, insulin-like growth factor I) that may further alter the function of tubular cells. Moreover, angiotensin II also stimulates uptake of ultrafiltered proteins into tubular cells and enhances the production of proinflammatory and profibrotic cytokines within the cells. Migration of macrophages and other inflammatory cells into the tubulointerstitium occurs. Increased synthesis and decreased turnover of extracellular matrix proteins in tubular cells and interstitial fibroblasts contribute to interstitial fibrosis. In addition, under locally high concentrations of angiotensin II and TGF-beta1, tubular cells may change their phenotype and become fibroblasts by a process called epithelial to mesenchymal transition (EMT) which contributes to interstitial fibrosis and tubular atrophy because of vanishing epithelia cells. An alternative explanation for the development of albuminuria in diabetic nephropathy that involves primarily an abnormality in tubular handling of ultrafiltered proteins has also been suggested, but these changes are not necessarily exclusive of the altered properties of glomerular ultrafiltration barrier.
There is an increasing interest in using poems and novels as a powerful resource to teach medical students ethical and professional behavior, virtues, and to illustrate the complexity of the ...doctor-patient relationship. This approach as part of a narrative medicine provides a framework for approaching a patient's problems more holistically and also offers a method for addressing existential inner qualities such as grief, hope, and despair that are part of illnesses. Occasionally, operas (mainly Italian) have also been used for this purpose. I however, propose that medical students may learn a lot from a deeper confrontation with the operas from the German composer Richard Wagner (1813-1883). Certainly, Wagner had a rather self-centered personality, also known for his notorious nationalistic and anti-Semitic essays, but his complete Gesamtkunstwerk (total work of art) encompasses almost every human feeling, conflict, and psychological problem including suffering, compassion, redemption, etc. Wagner's opera somewhat reflected his unsteady life. Wagner was convinced that his art could fill the void left by the retreat of traditional religion, suggesting that humanity may achieve freedom through the perception of beauty uniting communities through shared aesthetic experience. Not a very modest approach and not a very likable character, but a great composer. After a short biography, I will provide some (because of the complexity of the subject, naturally limited) arguments on what medical students can learn from Wagner operas, even though I am convinced that Wagner and his music are not easy to digest, even for experienced opera lovers.
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. Different types of renal cells undergo different pathophysiological changes induced by TGF-β, leading to apoptosis, hypertrophy and abnormalities of podocyte foot processes, which ultimately result in renal dysfunction. In this review, we describe the effects of TGF-β on different renal cell types and the means by which TGF-β participates in the pathomechanisms of glomerular and tubulointerstitial diseases.
PDF
