FSGS: from pathogenesis to the histological lesion
13
Citation
11
Reference
10
Related Paper
Citation Trend
Keywords:
Etiology
Pathogenesis
Focal and segmental glomerulosclerosis (FSGS) is a common glomerular lesion and a significant cause of end-stage renal disease (ESRD). FSGS lesions result from damage to glomerular epithelial cells called podocytes, a key cell type involved in glomerular filtration. Mutations in the ACTN4 gene, encoding an actin-crosslinking protein, are causative of late-onset familial FSGS in humans. We have developed a mouse model of FSGS by expressing a high-affinity variant of a-actinin-4 (K256E) in a podocyte-specific manner. Transgenic mice display podocyte damage, subsequent loss of serum proteins into the urine (proteinuria), and glomerular sclerosis, similar to that observed in human patients. In cultured podocytes, a-actinin-4 is mislocalized to stable actin-rich structures, which impairs cytoskeletal-dependent processes such as cell spreading and migration. We have also demonstrated that binding of a-actinin-4 to filamentous actin is regulated by calcium and phosphoinositides. Binding of calcium decreases the association of a-actinin-4 with actin, while binding of PIP2 and PIP3 enhances this interaction. High-affinity variants of a-actinin-4 are very static compared to the wildtype protein, and are insensitive to regulation by calcium or phosphoinositides. Such cytoskeletal dysfunction severely impairs the podocyte's ability to withstand mechanical stretch, a mimic of the distensive forces exerted on the podocytes in vivo. Although much insight has recently been gained into the biology of the podocyte, treatments for FSGS and other glomerular disorders remain few and ineffective. Further studies into the mechanisms involved in regulating the podocyte cytoskeleton in healthy and diseased states will surely lead to novel therapeutic interventions.
Actinin
Glomerulosclerosis
Cite
Citations (0)
Glomerulosclerosis
Minimal change disease
Cite
Citations (0)
IntroductionDuring glomerular diseases, podocyte-specific pathways can modulate the intensity of histological disease and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of kidney diseases. The Janus Kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently detailed in intrinsic kidney cells.MethodsWe describe STAT5 expression in human kidney biopsies from patients with focal and segmental glomerulosclerosis (FSGS) and studied mice with a podocyte-specific Stat5 deletion in experimental glomerular diseases.ResultsHere, we show, for the first time, that STAT5 is activated in human podocytes in FSGS. Additionally, podocyte-specific Stat5 inactivation aggravates the structural and functional alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of autophagic flux. Finally, Interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes and its administration alleviates glomerular injury in vivo by maintaining autophagic flux in podocytes.ConclusionIn conclusion, activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS.
STAT5
Glomerulosclerosis
Cite
Citations (2)
Focal segmental glomerulosclerosis (FSGS) is an aggressive disease often leading to renal failure. It might be difficult to distinguish FSGS from minimal change disease (MCD) when renal biopsies from patients with nephrotic syndrome do not indicate sclerotic lesions. Based on the rat model study, reducing podocyte density (average podocyte number per glomerular volume), which suggests relative podocyte depletion, could be seen in FSGS, but not MCD. Here, we compared the following histological parameters of FSGS and MCD in renal biopsy specimens of nephrotic patients.
Minimal change disease
Glomerulosclerosis
Cite
Citations (0)
Purpose of review Focal segmental glomerulosclerosis (FSGS) is a disease with diverse histologic patterns and etiologic associations. Genetic, toxic, infectious and inflammatory mediators have been identified. This review will focus on new evidence supporting the potential mechanistic basis underlying the histologic variants and their clinical relevance. Recent findings Evidence from animal models and in-vitro studies suggests that injury inherent within or directed to the podocyte is a central pathogenetic factor. Disruption of signaling from any of the podocyte's specialized membrane domains, including slit diaphragm, apical and basal membranes, or originating at the level of the actin cytoskeleton, may promote the characteristic response of foot process effacement. Irreversible podocyte stress leading to podocyte depletion through apoptosis or detachment is a critical mechanism in most forms of FSGS. In the collapsing variant, podocyte dysregulation leads to podocyte dedifferentiation and glomerular epithelial cell proliferation. Summary Translation studies in humans and new evidence from animal models have provided mechanistic insights into the diverse phenotypes of FSGS.
Slit diaphragm
Minimal change disease
Glomerulosclerosis
Cite
Citations (134)
Podocalyxin
Nephrin
Glomerulosclerosis
Nephrosis
Cite
Citations (211)
<b><i>Background:</i></b> Focal segmental glomerulosclerosis (FSGS) is a histologic pattern characterized by focal glomerular scarring, which often progresses to systemic and diffuse glomerulosclerosis. Previous studies have emphasized that the initiation of classic FSGS occurs in podocytes. The dysfunction and loss of podocytes have been associated with the development of proteinuria and the progression of various diseases. In addition, primary, secondary, and genetic FSGS are caused by different mechanisms of podocyte injury. <b><i>Summary:</i></b> The potential sources and mechanism of podocyte supplementation are the focus of our current research. Increasing attention has been paid to the role played by parietal epithelial cells (PECs) during the progression of FSGS. PECs are not only the primary influencing factors in glomerulosclerosis lesions but also have repair abilities, which remain a focus of debate. Notably, other resident glomerular cells also play significant roles in the progression of this disease. <b><i>Key Message:</i></b> In this review, we focus on the mechanism of scarring in FSGS and discuss current and potential therapeutic strategies.
Glomerulosclerosis
Minimal change disease
Cite
Citations (10)
Glomerulosclerosis
Cite
Citations (131)
Minimal change disease
Membranous Nephropathy
Glomerulosclerosis
Cite
Citations (58)
TRPC6
Glomerulosclerosis
Cite
Citations (52)