Braf signaling pathway inhibition, podocyte injury, and nephrotic syndrome american journal of kidney diseases. We previously found that the glomerular expression of sirtuin1 sirt1 is reduced in human diabetic glomeruli and that the podocyte specific loss of sirt1 aggravated albuminuria and worsened kidney disease progression in diabetic mice. The gfb is composed of glomerular endothelium, basement membrane, and podocytes. Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. Podocyte damage or loss is an early symptom of many kidney diseases presenting clinically with proteinuria with or without nephrotic syndrome and renal failure owing to glomerulosclerosis.
Here, we report that sonic hedgehog shh is the mediator that connects podocyte damage to. Podocyte injury is therefore a key determinant of glomerular diseases and esrd. Damage to the glomerular podocytes, is one of the first hallmarks of ckd. Glomerular endothelial cell injury and cross talk in diabetic kidney disease jia fu,1 kyung lee,2 peter y. Podocyte histone deacetylase activity regulates murine and. Podocyte injury elicits loss and recovery of cellular.
The integrity of glomerular podocytes is central to the pathogenesis of proteinuric kidney disease, but the mechanisms underlying podocyte injury remain poorly understood. In addition to sick podocytes and their detachment, our understanding of glomerular responses following podocyte loss needs to address the pathways from podocyte injury to sclerosis. Podocyturia may be an expression of glomerular disease and is evaluated using urinary podocytespecific molecules. Glomerular podocytes in kidney health and disease the lancet. From podocyte biology to novel cures for glomerular disease. Indeed, podocyte injury may be prominent in two major presentations. Tubular injury in glomerular disease kidney international. An injured podocyte reveals cytoplasmic blebs, protein droplets, and expansion of subpodocyte space, which are the results of podocyte stresses. Podocyte histone deacetylase activity inhibition as a. Proteinuria, a hallmark of renal glomerular diseases, indicates injury to the glomerular filtration barrier gfb. Podocyte dysfunction is central to the underlying pathophysiology of many common glomerular diseases, including diabetic nephropathy, glomerulonephritis and genetic forms of nephrotic syndrome. Epigenetic regulation of rcan1 expression in kidney. Role of podocytes and podocyteassociated biomarkers in. Podocyte lysosome dysfunction in chronic glomerular diseases.
Advancing understanding and treatment of glomerular disease. Trpc6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases daria v. From the periphery of the glomerular capillary wall toward the center of disease. Disruption of the filtration slits or destruction of the podocytes can lead to massive proteinuria, where large amounts of protein are lost from the blood. Correlation study of podocyte injury and kidney function.
Injury to other components of the glomerular filtration barrier, such as gen and gbm. Minimal change disease mcd, focal segmental glomerular sclerosis fsgs, membranous nephropathy mn, and iga nephropathy igan cause proteinuria by means of glomerular podocyte injury, most likely related to immune dysregulation, although the exact mechanisms are still unknown 3,4. Angiotensin iimediated myh9 downregulation causes structural and functional podocyte injury in diabetic kidney disease skip to main content thank you for visiting. Glomerular disease may be caused by an infection or a drug that is harmful to your kidneys. Chuang,2 zhihong liu,1 and john cijiang he2 1research institute of nephrology, jinling hospital, nanjing university school of medicine, jiangsu, china.
Secondary glomerular disease jeremy levy abstract secondary glomerular diseases are common worldwide and can manifest in many ways. However, previous studies have revealed that the basal level of mtorc1 activity is required for maintaining the normal function of podocytes. Glomerular endothelial cell injury and cross talk in. Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. Key features of podocytes are interdigitated foot processes with filtration slits in. Foot process detachment or effacement is a key feature of podocyte injury 4, 15. Demonstrable protective effects from captopril occur, despite indiscernible preservation or.
In other cases, it may be caused by a disease that affects the entire body, like diabetes or lupus. However, because we used global rcan1 knockout mice in our study, we cannot rule out the systemic effects of rcan1 loss on podocyte injury. Illustration of the consequences of podocyte injury. Conversely, the induction of tyro3 overexpression specifically in podocytes significantly attenuated albuminuria and kidney injury in mice with dkd, adrn, and hivassociated nephropathy hivan. Increased podocyte sirtuin1 function attenuates diabetic. Jci insight tyro3 is a podocyte protective factor in. Podocyte lysosome dysfunction in chronic glomerular. Plasminogenuria is associated with podocyte injury, edema. Trpc6 channel as an emerging determinant of the podocyte. Gold nanoparticles attenuate albuminuria by inhibiting.
Podocyte loss and progressive glomerular injury in type ii. Glomerular diseases include many conditions with many different causes. The contribution of tubular injury to loss of remnant kidney function. Understanding glomerular diseases national kidney foundation. This article discusses the technical problems of detection and quantification of podocyturia using immunofluorescent staining of specific proteins, urinary podocyte culture. Podocyte injury and loss contribute to the progression of glomerular diseases, including diabetic kidney disease. One of the significant events in the pathogenesis of dn is the progressive podocyte injury, which expresses the recession of the podocyte foot processes that lead to defacement, loss of slit diaphragm proteins, detachment, and finally cell apoptosis 9. On the basis of our findings, we hypothesize that the ability of podocytes to maintain or recover cellular force transmission may be central to preventing detachment. Together with glomerular endothelial cells gen and glomerular basement membrane gbm, podocytes form the glomerular filtration barrier in the kidney figure 3. Since podocytes are terminally differentiated with minimal capacity to selfreplicate, they are. Podocyte injury is of pathogenetic and prognostic significance in human glomerular disease.
Glomerular disease is characterized by proteinuria and glomerulosclerosis, two pathologic features caused by podocyte injury and mesangial cell activation, respectively. Podocyte injury and its consequences kidney international. In the following study, we analyzed the correlation between podocyte injury and kidney function in patients with aki. Podocyte loss and progressive glomerular injury in type ii diabetes. While it is well established that the progression of primary glomerular disease induces tubulointerstitial lesions, how tubular injury triggers glomerular damage is poorly understood. Braf signaling pathway inhibition, podocyte injury, and. We hypothesized that podocyte prostaglandin e2 pge2 receptors contribute to the progression of glomerular injury in models of ckd. Direct podocyte injury contributes to the onset and progression of glomerular diseases such as minimal change disease mcd, focal segmental glomerular sclerosis fsgs, diabetic nephropathy, and hivassociated nephropathy hivan. Recently, podocyte 16 loss and podocyturia 17 has been recognized as a potential diagnostic marker of the severity of glomerular disease. Bacterial and viral infections, especially hepatitis and hiv, can cause a variety of patterns of glomerular injury often presenting with nephrotic syndrome, as can tumours and drugs. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive footprocess effacement, and glomerular endothelial injury. Because podocyte injury plays a key role in dkd pathogenesis, podocyte associated biomarkers may play an important role in the early diagnosis of kidney damage in the setting of diabetes. Chronic kidney disease affects more than 10% of the worlds population.
Endothelin and podocyte injury in chronic kidney disease. In particular, podocyte function is dependent on the cells actin cytoskeleton. Although the inciting injury to the podocyte may vary between various glomerular diseases, the inevitable consequence of podocyte injury results in their loss, leading to progressive kidney disease. Glomerulosclerosis in combination with loss of glomerular filtration also typically occurs in the aging human kidney. Injury to other components of the glomerular filtration barrier, such. For populations at risk, the mechanisms of podocyte.
However, whether these two events are linked remains elusive. Podocyte loss is a general mechanism of glomerular dysfunction that initiates and drives the progression of chronic kidney disease, which affects 10% of the world population. As these genetically modified mice developed podocyte loss, glomerulosclerosis, and progressive kidney failure, which is similar to progression of human glomerular diseases, we used this model to pursue differentially expressed genes following glomerular injury through rna profiling of control and tln1 flfl podrtta tetocre mouse glomeruli isolated 2 weeks after completion of. As the major degradative components of cells, the normal function of lysosomes is necessary to renew cellular activity and maintain the structural and functional integrity of. Podocyte injury causes a variety of cellular and structural responses in the glomerulus. In addition, we showed that rcan1 loss led to aggravated podocyte injury and glomerular disease in mice with adrn, further confirming an in vivo role of rcan1 in maintaining normal podocyte function. Genetic deletion of mtorc1 in podocytes may cause the disruption of autophagic. Tyro3 is a podocyte protective factor in glomerular disease. An initial study examined renal structure at 10 and 25 weeks after fivesixths renal ablationx22. Most glomerular diseases in which the podocyte is the target of injury are not associated with podocyte proliferation 5,6. Podocyte injury in glomerular disease questions and study. Podocyte injury in glomerular diseases mirjana sabljar matovinovic podocytes are injured in diabetic and nondiabetic renal diseases figure 3.
Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Animal models indicate that the agedependent development of glomerulosclerosis is due to a loss of podocytes 8, 9. We applied the serial section technique to examine disease progression in experimental glomerular disease. At present, whether the podocyte injury is involved with the pathophysiologic process of aki and the relations between the marker molecules of podocyte injury and the changes of kidney function of aki are not yet precisely reported. Most of these studies have profiled structural changes that culminate in. Sphingomyelinaselike phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. Jci insight tubular injury triggers podocyte dysfunction. Although medications are a widely known cause of tubulointerstitial damage, drugrelated glomerular. Jcm free fulltext podocyte injury in lupus nephritis. Jci insight sonic hedgehog connects podocyte injury to. Perazella abstract drugs and toxins frequently are associated with the development of various types of acute kidney disease and ckd. Proteinuric chronic kidney disease ckd remains a major health problem worldwide. Despite compelling evidence identifying the podocyte as the key injury mediator, cellspecific therapies are not clinically available, and validated therapeutic targets are scarce.
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