Recurrent Focal Segmental Glomerulosclerosis

Verani, Regina; Hawkins, Edith P.

doi:10.1159/000167173

Cited by 57 publications

(6 citation statements)

References 14 publications

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“…Second, we performed a separate analysis of cortical versus juxtamedullary nephrons, stimulated by the observation that the latter are more severely injured in many disorders including AN 22 , 23 , 24 and are more frequently and more severely affected by glomerulosclerosis. 25 , 26 Our data suggest that juxtamedullary nephrons, which represent only 20% of glomeruli, harbor more podocytes because they are larger, 27 , 28 , 29 face substantially more ADR-induced podocyte loss, and recover less from injury because they are endowed with less Pax2+ progenitors per podocyte. In contrast, cortical nephrons are smaller but much more numerous, 27 , 28 have less podocytes, and lose only few podocytes during AN, which they can recover more easily because cortical nephrons have more Pax2+ progenitors per podocyte.…”

Section: Discussionmentioning

confidence: 70%

CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism

Romoli¹,

Angelotti

Antonelli

et al. 2018

Kidney International

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Insufficient podocyte regeneration after injury is a central pathomechanism of glomerulosclerosis and chronic kidney disease. Podocytes constitutively secrete the chemokine CXCL12, which is known to regulate homing and activation of stem cells; hence we hypothesized a similar effect of CXCL12 on podocyte progenitors. CXCL12 blockade increased podocyte numbers and attenuated proteinuria in mice with Adriamycin-induced nephropathy. Similar studies in lineage-tracing mice revealed enhanced de novo podocyte formation from parietal epithelial cells in the setting of CXCL12 blockade. Super-resolution microscopy documented full integration of these progenitor-derived podocytes into the glomerular filtration barrier, interdigitating with tertiary foot processes of neighboring podocytes. Quantitative 3D analysis revealed that conventional 2D analysis underestimated the numbers of progenitor-derived podocytes. The 3D analysis also demonstrated differences between juxtamedullary and cortical nephrons in both progenitor endowment and Adriamycin-induced podocyte loss, with more robust podocyte regeneration in cortical nephrons with CXCL12 blockade. Finally, we found that delayed CXCL12 inhibition still had protective effects. In vitro studies found that CXCL12 inhibition uncoupled Notch signaling in podocyte progenitors. These data suggest that CXCL12-driven podocyte-progenitor feedback maintains progenitor quiescence during homeostasis, but also limits their intrinsic capacity to regenerate lost podocytes, especially in cortical nephrons. CXCL12 inhibition could be an innovative therapeutic strategy in glomerular disorders.

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Section: Discussionmentioning

confidence: 70%

CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism

Romoli¹,

Angelotti

Antonelli

et al. 2018

Kidney International

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“…2,3 These studies, confirmed in human FSGS that recurs post kidney transplant 4 , have shown that podocyte injury exemplified by cell body attenuation, foot process effacement, pseudocyst formation and microvillous transformation, is the earliest feature of FSGS. In human FSGS, these electron microscopic findings may be seen weeks to months prior to the development of visible lesions by light microscopy.…”

Section: Morphological Studies Place Podocytes At the Center Of Fsgsmentioning

confidence: 89%

The Pathogenesis of Focal Segmental Glomerulosclerosis

Jefferson

Shankland

2014

Advances in Chronic Kidney Disease

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Focal segmental glomerulosclerosis (FSGS) is a histological pattern of injury on renal biopsy that can arise from a diverse range of causes and mechanisms. Although primary and secondary forms are described based on the underlying cause, there are many common factors that underlie the development of this segmental injury. In this review we will describe the currently accepted model for the pathogenesis of classic FSGS and review the data supporting this model. Although the podocyte is considered the major target of injury in FSGS, we will also highlight the contributions of other resident glomerular cells in the development of FSGS.

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“…4 Plasmapheresis has been successfully used to treat a number of transplant recipients with early recurrence of FSGS. 5 Interestingly, successful retransplantation of a kidney allograft from a patient with recurrent primary FSGS who did not respond to therapy to a patient whose primary kidney disease was not FSGS, has been reported.…”

Section: Clinical Settingmentioning

confidence: 99%

Causes and pathogenesis of focal segmental glomerulosclerosis

2014

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Focal segmental glomerulosclerosis (FSGS) describes both a common lesion in progressive kidney disease, and a disease characterized by marked proteinuria and podocyte injury. The initial injuries vary widely. Monogenetic forms of FSGS are largely due to alterations in structural genes of the podocyte, many of which result in early onset of disease. Genetic risk alleles in apolipoprotein L1 are especially prevalent in African Americans, and are linked not only to adult-onset FSGS but also to progression of some other kidney diseases. The recurrence of FSGS in some transplant recipients whose end-stage renal disease was caused by FSGS points to circulating factors in disease pathogenesis, which remain incompletely understood. In addition, infection, drug use, and secondary maladaptive responses after loss of nephrons from any cause may also cause FSGS. Varying phenotypes of the sclerosis are also manifest, with varying prognosis. The so-called tip lesion has the best prognosis, whereas the collapsing type of FSGS has the worst prognosis. New insights into glomerular cell injury response and repair may pave the way for possible therapeutic strategies.

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Recurrent Focal Segmental Glomerulosclerosis

Cited by 57 publications

References 14 publications

CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism

CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism

The Pathogenesis of Focal Segmental Glomerulosclerosis

Causes and pathogenesis of focal segmental glomerulosclerosis

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