Jci insight sonic hedgehog connects podocyte injury to. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive footprocess effacement, and glomerular endothelial injury. However, previous studies have revealed that the basal level of mtorc1 activity is required for maintaining the normal function of podocytes. 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. Despite compelling evidence identifying the podocyte as the key injury mediator, cellspecific therapies are not clinically available, and validated therapeutic targets are scarce. While it is well established that the progression of primary glomerular disease induces tubulointerstitial lesions, how tubular injury triggers glomerular damage is poorly understood.
Jci insight tubular injury triggers podocyte dysfunction. Epigenetic regulation of rcan1 expression in kidney. 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. The gfb is composed of glomerular endothelium, basement membrane, and podocytes. Jcm free fulltext podocyte injury in lupus nephritis. In other cases, it may be caused by a disease that affects the entire body, like diabetes or lupus.
Glomerulosclerosis in combination with loss of glomerular filtration also typically occurs in the aging human kidney. Trpc6 channel as an emerging determinant of the podocyte. Podocyte histone deacetylase activity regulates murine and. Podocyturia may be an expression of glomerular disease and is evaluated using urinary podocytespecific molecules.
Podocyte loss and progressive glomerular injury in type ii diabetes. Podocyte loss and progressive glomerular injury in type ii. From podocyte biology to novel cures for glomerular disease. Damage to the glomerular podocytes, is one of the first hallmarks of ckd.
Understanding glomerular diseases national kidney foundation. Together with glomerular endothelial cells gen and glomerular basement membrane gbm, podocytes form the glomerular filtration barrier in the kidney figure 3. However, because we used global rcan1 knockout mice in our study, we cannot rule out the systemic effects of rcan1 loss on podocyte injury. From the periphery of the glomerular capillary wall toward the center of disease. Podocyte injury in glomerular diseases mirjana sabljar matovinovic podocytes are injured in diabetic and nondiabetic renal diseases figure 3. Braf signaling pathway inhibition, podocyte injury, and. Demonstrable protective effects from captopril occur, despite indiscernible preservation or. Illustration of the consequences of podocyte injury. Foot process detachment or effacement is a key feature of podocyte injury 4, 15. Glomerular endothelial cell injury and cross talk in diabetic kidney disease jia fu,1 kyung lee,2 peter y. Increased podocyte sirtuin1 function attenuates diabetic. Perazella abstract drugs and toxins frequently are associated with the development of various types of acute kidney disease and ckd. Proteinuria, a hallmark of renal glomerular diseases, indicates injury to the glomerular filtration barrier gfb.
We hypothesized that podocyte prostaglandin e2 pge2 receptors contribute to the progression of glomerular injury in models of ckd. For populations at risk, the mechanisms of podocyte. Correlation study of podocyte injury and kidney function. Podocyte injury is therefore a key determinant of glomerular diseases and esrd. Proteinuric chronic kidney disease ckd remains a major health problem worldwide. 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. Conversely, the induction of tyro3 overexpression specifically in podocytes significantly attenuated albuminuria and kidney injury in mice with dkd, adrn, and hivassociated nephropathy hivan.
Podocyte lysosome dysfunction in chronic glomerular diseases. Injury to other components of the glomerular filtration barrier, such. 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. Angiotensin iimediated myh9 downregulation causes structural and functional podocyte injury in diabetic kidney disease skip to main content thank you for visiting. Following specific podocyte injury captopril protects. In the following study, we analyzed the correlation between podocyte injury and kidney function in patients with aki. 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. 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. The contribution of tubular injury to loss of remnant kidney function. Tubular injury in glomerular disease kidney international. Role of podocytes and podocyteassociated biomarkers in. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. An injured podocyte reveals cytoplasmic blebs, protein droplets, and expansion of subpodocyte space, which are the results of podocyte stresses.
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. Glomerular disease is characterized by proteinuria and glomerulosclerosis, two pathologic features caused by podocyte injury and mesangial cell activation, respectively. Chuang,2 zhihong liu,1 and john cijiang he2 1research institute of nephrology, jinling hospital, nanjing university school of medicine, jiangsu, china. Glomerular endothelial cell injury and cross talk in. Most of these studies have profiled structural changes that culminate in. Secondary glomerular disease jeremy levy abstract secondary glomerular diseases are common worldwide and can manifest in many ways. Gold nanoparticles attenuate albuminuria by inhibiting. 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. Jci insight tyro3 is a podocyte protective factor in. Glomerular disease may be caused by an infection or a drug that is harmful to your kidneys. Podocyte injury and loss contribute to the progression of glomerular diseases, including diabetic kidney disease. An initial study examined renal structure at 10 and 25 weeks after fivesixths renal ablationx22.
Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. 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. Podocyte dysfunction is central to the underlying pathophysiology of many common glomerular diseases, including diabetic nephropathy, glomerulonephritis and genetic forms of nephrotic syndrome. 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. Ilatovskaya1 and x alexander staruschenko1,2 1department of physiology, medical college of wisconsin, milwaukee, wisconsin. This article discusses the technical problems of detection and quantification of podocyturia using immunofluorescent staining of specific proteins, urinary podocyte culture. Plasminogenuria is associated with podocyte injury, edema.
Glomerular podocytes in kidney health and disease the lancet. Recently, podocyte 16 loss and podocyturia 17 has been recognized as a potential diagnostic marker of the severity of glomerular disease. Indeed, podocyte injury may be prominent in two major presentations. In particular, podocyte function is dependent on the cells actin cytoskeleton.
Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. Chronic kidney disease affects more than 10% of the worlds population. Key features of podocytes are interdigitated foot processes with filtration slits in. We applied the serial section technique to examine disease progression in experimental glomerular disease. 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. Podocyte injury is of pathogenetic and prognostic significance in human glomerular disease. Genetic deletion of mtorc1 in podocytes may cause the disruption of autophagic. Most glomerular diseases in which the podocyte is the target of injury are not associated with podocyte proliferation 5,6. Braf signaling pathway inhibition, podocyte injury, and nephrotic syndrome american journal of kidney diseases. 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 lysosome dysfunction in chronic glomerular. Podocyte injury causes a variety of cellular and structural responses in the glomerulus. Glomerular diseases include many conditions with many different causes. Podocyte injury elicits loss and recovery of cellular. Sphingomyelinaselike phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. Injury to other components of the glomerular filtration barrier, such as gen and gbm. 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.
Since podocytes are terminally differentiated with minimal capacity to selfreplicate, they are. Endothelin and podocyte injury in chronic kidney disease. Here, we report that sonic hedgehog shh is the mediator that connects podocyte damage to. 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. However, whether these two events are linked remains elusive. Advancing understanding and treatment of glomerular disease. Tyro3 is a podocyte protective factor in glomerular disease. 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. Podocyte histone deacetylase activity inhibition as a. 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. Podocyte injury and its consequences kidney international. Podocyte injury in glomerular disease questions and study. Urine podocytes and podocyte specific proteins can serve as urinary markers for early diagnosis of dkd 65, 66. Although medications are a widely known cause of tubulointerstitial damage, drugrelated glomerular.
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