Ion channels and channelopathies in glomeruli

Physiological Reviews, Год журнала: 2022, Номер 103(1), С. 787 - 854

Опубликована: Авг. 25, 2022

An essential step in renal function entails the formation of an ultrafiltrate that is delivered to tubules for subsequent processing. This process, known as glomerular filtration, controlled by intrinsic regulatory systems and paracrine, neuronal, endocrine signals converge onto cells. In addition, characteristics fluid flow, such filtration rate fraction, play important role determining blood flow rest kidney. Consequently, disease processes initially affect glomeruli are most likely lead end-stage kidney failure. The cells comprise filter, especially podocytes mesangial cells, express many different types ion channels regulate aspects cell cellular responses local environment, changes capillary pressure. Dysregulation channels, TRPC6, can devastating diseases, a number including TRPC5, various ionotropic receptors, promising targets drug development. review discusses structure processes. It also describes plasma membrane have been identified physiological pathophysiological contexts which they operate, pathways regulated dysregulated. contributions these processes, focal segmental glomerulosclerosis (FSGS) diabetic nephropathy, well development drugs target discussed.

Язык: Английский

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Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Сен. 19, 2023

The pathogenetic mechanisms underlying the onset and post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex remain yet to be fully elucidated. However, a growing body evidence emphasizes pivotal role immune system in both initiating perpetuating disease. Extensive investigations, encompassing experimental models patient studies, have implicated T cells, B complement as crucial actors pathogenesis FSGS, with various molecules being proposed potential “circulating factors” contributing disease its post kidney-transplantation. In this review, we critically assessed existing literature identify essential pathways for comprehensive characterization FSGS. Recent discoveries shed further light on intricate interplay between these mechanisms. We present an overview current understanding engagement distinct cells FSGS while highlighting critical knowledge gaps that require attention. A thorough holds noninvasive biomarkers can accurately patients at high risk recurrence. Such pave way development targeted personalized therapeutic approaches management

Язык: Английский

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Podocyte-targeted therapies — progress and future directions

Nature Reviews Nephrology, Год журнала: 2024, Номер 20(10), С. 643 - 658

Опубликована: Май 9, 2024

Язык: Английский

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Advances in Focal Segmental Glomerulosclerosis Treatment From the Perspective of the Newest Mechanisms of Podocyte Injury

Drug Design Development and Therapy, Год журнала: 2025, Номер Volume 19, С. 857 - 875

Опубликована: Фев. 1, 2025

Podocyte injury was widely recognized as a fundamental mechanism driving the progression of focal segmental glomerulosclerosis (FSGS). Recent research has therefore focused on development targeted therapies aimed at disrupting specific pathogenic signaling cascades within podocytes, resulting in noteworthy advancements. The role mechanisms such alterations actin cytoskeleton, oxidative stress, mitochondrial dysfunction, and inadequate autophagy microenvironment podocyte have garnered increasing attention. Corresponding medications Abatacept, chemokine receptor (CCR) inhibitors, CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), adenosine monophosphate-activated protein kinase (AMPK) activators, Adalimumab are currently under investigation. Notably, some Rituximab Sparsentan, may simultaneously target multiple downstream mechanisms, Furthermore, exploring molecular strategies for established developing novel treatments guided by biomarkers Anti-CD40 antibody, blood microRNA, urinary tumor necrosis factor-alpha (TNF-α) provide additional therapeutic avenues patients with FSGS.

Язык: Английский

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KDOQI US Commentary on the 2021 KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases

American Journal of Kidney Diseases, Год журнала: 2023, Номер 82(2), С. 121 - 175

Опубликована: Июнь 21, 2023

Язык: Английский

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Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study

Transplantation, Год журнала: 2024, Номер unknown

Опубликована: Апрель 1, 2024

Background. Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after transplantation. Recurrent FSGS (rFSGS) associated with poor allograft patient outcomes. Bleselumab, fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40−related processes in FSGS, potentially preventing rFSGS. Methods. A phase 2a, randomized, multicenter, open-label study adult recipients (aged ≥18 y) living or deceased donor transplant history biopsy-proven primary FSGS. The assessed the efficacy bleselumab combined tacrolimus corticosteroids as maintenance immunosuppression prevention rFSGS >12 mo posttransplantation, versus standard care (SOC) comprising tacrolimus, mycophenolate mofetil, corticosteroids. All patients received basiliximab induction. endpoint was rFSGS, defined proteinuria (protein-creatinine ratio ≥3.0 g/g) death, graft loss, loss to follow-up imputed through 3 posttransplant. Results. Sixty-three were followed for 12 posttransplantation. Relative decrease occurrence SOC 40.7% (95% confidence interval, −89.8 26.8; P = 0.37; absolute 12.7% [95% −34.5 9.0]). Central-blinded biopsy review found relative (absolute) decreases 10.9% (3.9%), 17.0% (6.2%), 20.5% (7.5%) at 3, 6, posttransplant, respectively; these differences not statistically significant. Adverse events similar both treatments. No deaths occurred during study. Conclusions. In at-risk recipients, numerically reduced SOC, but no notable difference observed.

Язык: Английский

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Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety

Kidney Medicine, Год журнала: 2024, Номер 6(6), С. 100833 - 100833

Опубликована: Апрель 26, 2024

Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist (DEARA) examined in the ongoing phase 2 DUET trial for focal segmental glomerulosclerosis (FSGS). In 8-week double-blind period, sparsentan resulted greater proteinuria reduction versus irbesartan. We report long-term efficacy and safety of during open-label extension over more than 4 years.

Язык: Английский

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Rituximab in steroid-resistant nephrotic syndrome: antinephrin antibodies and predictors of response

Kidney International, Год журнала: 2025, Номер 107(3), С. 575 - 576

Опубликована: Фев. 19, 2025

Язык: Английский

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Anti-Nephrin Antibodies in Adult Chinese Patients with Minimal Change Disease and Primary Focal Segmental Glomerulosclerosis

Kidney International, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Btg2 Promotes Focal Segmental Glomerulosclerosis via Smad3‐Dependent Podocyte‐Mesenchymal Transition

Advanced Science, Год журнала: 2023, Номер 10(32)

Опубликована: Сен. 25, 2023

Podocyte injury plays a critical role in the progression of focal segmental glomerulosclerosis (FSGS). Here, it is reported that B-cell translocation gene 2 (Btg2) promotes Adriamycin (ADR)-induced FSGS via Smad3-dependent podocyte-mesenchymal transition. It found patients and animal models, Btg2 markedly upregulated by podocytes correlated with progressive renal injury. Podocyte-specific deletion protected against onset proteinuria ADR-treated mice along inhibition EMT markers such as α-SMA vimentin while restoring epithelial marker E-cadherin. In cultured MPC5 podocytes, overexpression largely promoted ADR TGF-β1-induced fibrosis, which further enhanced overexpressing but blocked disrupting Btg2. Mechanistically, rapidly induced TGF-β1 then bound Smad3 not Smad2 to promote signaling podocyte EMT, again exacerbated deleting podocytes. Interestingly, blockade inhibitor SIS3 also capable inhibiting expression Btg2-mediated revealing TGF-β/Smad3-Btg2 circuit mechanism FSGS. conclusion, pathogenic pathway.

Язык: Английский

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