Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G
-M phase, with secretion ...of profibrotic factors. Here, we show that epithelial cells in the G
-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G
-M arrest in PTCs and up-regulated TASCC formation. PTC TASCC formation was also present in humans with CKD. Prevention of TASCC formation in cultured PTCs blocked secretion of profibrotic factors. PTC-specific knockout of a key TASCC component reduced the rate of kidney fibrosis progression in mice with CKD. CG1 induction and TASCC formation also occur in liver fibrosis. Deletion of CG1 reduced G
-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G
-M arrest is induced in kidney injury and how G
-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.
Abstract Primary focal segmental glomerulosclerosis (FSGS) leads to end-stage renal disease in a high proportion of cases. The recurrence of FSGS after kidney transplantation is frequent (20%–40%) ...and associated with poor graft survival. The pathophysiology of primary FSGS remains uncertain, but secretion of a circulating factor is suspected to play a key role in excessive glomerular permeability. The treatment of recurrence is still controversial, and most reports related to use of plasma exchange have been uncontrolled trials with relatively small groups of patients and conflicting results. Plasma exchange and protein immunoadsorption can markedly reduce urinary protein excretion and induce complete remission in some cases but usually fail to achieve sustained remission. Steroids and high-dose cyclosporine can reduce proteinuria based on their immunosuppressive properties and through stabilization of the podocyte actin cytoskeleton. Recent advances in our understanding of primary FSGS and podocyte function open the way to more targeted therapies. This review summarizes the therapeutic approach to FSGS recurrence.
Recent advances in genetic sequencing are transforming our approach to rare-disease care. Initially identified in cancer, gain-of-function mutations of the
gene are also detected in malformation ...mosaic diseases categorized as
-related disorders (PRDs). Over the past decade, new approaches have enabled researchers to elucidate the pathophysiology of PRDs and uncover novel therapeutic options. In just a few years, owing to vigorous global research efforts, PRDs have been transformed from incurable diseases to chronic disorders accessible to targeted therapy. However, new challenges for both medical practitioners and researchers have emerged. Areas of uncertainty remain in our comprehension of PRDs, especially regarding the relationship between genotype and phenotype, the mechanisms underlying mosaicism, and the processes involved in intercellular communication. As the clinical and biological landscape of PRDs is constantly evolving, this review aims to summarize current knowledge regarding
and its role in nonmalignant human disease, from molecular mechanisms to evidence-based treatments. Expected final online publication date for the
, Volume 25 is August 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Collapsing glomerulopathy is an aggressive kidney disease with rapid progression toward end-stage renal disease. Rare cases of de novo collapsing glomerulopathy have been reported during the ...post-transplant course and, in some instances, have been associated with renal graft vascular lesions. This finding raises the important question of whether ischemia could induce podocyte transdifferentiation, a hypothesis supported by evidence of hypoxia-inducible factor–dependent podocyte proliferation in HIV-associated nephropathy. We describe here 3 HIV-negative kidney transplant recipients in whom early graft biopsy performed in the vicinity of segmental graft infarction disclosed the typical features of glomerular collapse. Podocyte transdifferentiation was characterized by hallmark lesions, such as loss of mature podocyte phenotype, podocyte proliferation, and acquisition of a macrophage-like phenotype. Together, these data suggest that acute glomerular ischemia may lead to glomerular collapse in kidney transplants.
Acute kidney injury (AKI) affects over 13 million people worldwide annually and is associated with a 4-fold increase in mortality. Our lab and others have shown that DNA damage response (DDR) governs ...the outcome of AKI in a bimodal manner. Activation of DDR sensor kinases protects against AKI, while hyperactivation of DDR effector proteins, such as p53, induces cell death and worsens AKI. The factors that trigger DDR to switch from pro-repair to pro-cell death remain to be resolved. Here we investigated the role of interleukin 22 (IL-22), an IL-10 family member whose receptor (IL-22RA1) is expressed on proximal tubule cells (PTCs), in DDR activation and AKI. Using cisplatin and aristolochic acid (AA) induced nephropathy as models of DNA damage, we identified PTCs as a novel source of urinary IL-22. Functionally, IL-22 binding IL-22RA1 on PTCs amplified the DDR. Treating primary PTCs with IL-22 alone induced rapid activation of the DDR. The combination of IL-22 and either cisplatin- or AA-induced cell death in primary PTCs, while the same dose of cisplatin or AA alone did not. Global deletion of IL-22 protected against cisplatin- or AA-induced AKI, reduced expression of DDR components, and inhibited PTC cell death. To confirm PTC IL-22 signaling contributed to AKI, we knocked out IL-22RA1 specifically in kidney tubule cells. IL-22RA1ΔTub mice displayed reduced DDR activation, cell death, and kidney injury compared to controls. Thus, targeting IL-22 represents a novel therapeutic approach to prevent the negative consequences of the DDR activation while not interfering with repair of damaged DNA.
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Cette revue traite des syndromes hypertrophiques liées à une mutation somatique du gène PIK3CA. Cette entité nouvellement décrite englobe un grand nombre de syndromes dysmorphiques ayant comme point ...commun une mutation activatrice du gène PIK3CA. Les aspectes cliniques, diagnostics moléculaires et prise en charge thérapeutiques sont discutés.
This review presents an overview of a recently characterized spectrum of overgrowth syndrome: phosphoinositide-3 kinase (PI3K)-related overgrowth spectrum (PROS). This spectrum encompasses overgrowth syndromes associated with somatic mosaic activating PIK3CA mutations such as megalencephaly-capillary malformation (MCAP) syndrome, dysplatic megalencephaly (DMEG), congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, hemihyperplasia-multiple lipomatosis (HHML), fibroadipose overgrowth and Klippel-Trenaunay syndrome. Mosaic gain of function mutation in PIK3CA gene leads to abnormal AKT-mTOR pathway activation and is responsible of the clinical manifestations. Here, we summarize the current knowledge on this disorder.
PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA gene. There is no approved medical therapy for patients with PROS, and ...alpelisib, an approved PIK3CA inhibitor in oncology, showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient 1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations and good tolerability.
Molecular diagnostics is a cornerstone of modern precision medicine, broadly understood as tailoring an individual's treatment, follow-up, and care based on molecular data. In rare diseases (RDs), ...molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies. Due to decreasing DNA sequencing costs, genome sequencing (GS) is emerging as the primary method for precision diagnostics in RDs. Several ongoing European initiatives for precision medicine have chosen GS as their method of choice. Recent research supports the role for GS as first-line genetic investigation in individuals with suspected RD, due to its improved diagnostic yield compared to other methods. Moreover, GS can detect a broad range of genetic aberrations including those in noncoding regions, producing comprehensive data that can be periodically reanalyzed for years to come when further evidence emerges. Indeed, targeted drug development and repurposing of medicines can be accelerated as more individuals with RDs receive a molecular diagnosis. Multidisciplinary teams in which clinical specialists collaborate with geneticists, genomics education of professionals and the public, and dialogue with patient advocacy groups are essential elements for the integration of precision medicine into clinical practice worldwide. It is also paramount that large research projects share genetic data and leverage novel technologies to fully diagnose individuals with RDs. In conclusion, GS increases diagnostic yields and is a crucial step toward precision medicine for RDs. Its clinical implementation will enable better patient management, unlock targeted therapies, and guide the development of innovative treatments.
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