Glomerular Diseases

Bose, Bhadran; Cattran, Daniel C.

doi:10.2215/cjn.05810513

Cited by 71 publications

(72 citation statements)

References 53 publications

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“…We found that FSGS-linked ACTN4 mutants significantly reduced GRE reporter activity (Fig. 5A, lanes [3][4][5], and the reduction of GRE activities was also observed in GR-overexpressing cells (Fig. 5A, lanes 8 -10).…”

Section: Expression Of Gr␣ In Immortalized Hpcs and Primarymentioning

confidence: 69%

“…Recent studies in multiple experimental models have begun to explore the direct and indirect effects of NRs in renal cells to better utilize NR ligands as therapeutic agents for glomerular diseases such as minimalchange disease (MCD) and focal segmental glomerulosclerosis (FSGS) (1,2). Glucocorticoids (GCs) as a general class of steroids possess renoprotective activity in glomeruli (3-7); however, steroid resistance and systemic toxicity remain major issues for their long-term use (4). This is, in part, due to a lack of understanding of the mechanism underlying transcriptional regulation by the glucocorticoid receptor (GR␣) in podocytes, a key cell type in the glomerulus that forms the filtration barrier.…”

mentioning

confidence: 99%

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α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes

Zhao

Khurana

Charkraborty

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangGlucocorticoids are a general class of steroids that possess renoprotective activity in glomeruli through their interaction with the glucocorticoid receptor. However, the mechanisms by which glucocorticoids ameliorate proteinuria and glomerular disease are not well understood. In this study, we demonstrated that ␣ actinin 4 (ACTN4), an actin-cross-linking protein known to coordinate cytoskeletal organization, interacts with the glucocorticoid receptor (GR) in the nucleus of human podocytes (HPCs), a key cell type in the glomerulus critical for kidney filtration function. The GR-ACTN4 complex enhances glucocorticoid response element (GRE)-driven reporter activity. Stable knockdown of ACTN4 by shRNA in HPCs significantly reduces dexamethasone-mediated induction of GR target genes and GRE-driven reporter activity without disrupting dexamethasone-induced nuclear translocation of GR. Synonymous mutations or protein expression losses in ACTN4 are associated with kidney diseases, including focal segmental glomerulosclerosis, characterized by proteinuria and podocyte injury. We found that focal segmental glomerulosclerosis-linked ACTN4 mutants lose their ability to bind liganded GR and support GRE-mediated transcriptional activity. Mechanistically, GR and ACTN4 interact in the nucleus of HPCs. Furthermore, disruption of the LXXLL nuclear receptor-interacting motif present in ACTN4 results in reduced GR interaction and dexamethasone-mediated transactivation of a GRE reporter while still maintaining its actin-binding activity. In contrast, an ACTN4 isoform, ACTN4 (Iso), that loses its actin-binding domain is still capable of potentiating a GRE reporter. Dexamethasone induces the recruitment of ACTN4 and GR to putative GREs in dexamethasone-transactivated promoters, SERPINE1, ANGPLT4, CCL20, and SAA1 as well as the NF-B (p65) binding sites on GR-transrepressed promoters such as IL-1␤, IL-6, and IL-8. Taken together, our data establish ACTN4 as a transcriptional co-regulator that modulates both dexamethasone-transactivated and -transrepressed genes in podocytes.

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Section: Expression Of Gr␣ In Immortalized Hpcs and Primarymentioning

confidence: 69%

mentioning

confidence: 99%

α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes

Zhao

Khurana

Charkraborty

et al. 2017

Journal of Biological Chemistry

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“…), bu tedavinin yanında steroid tedavisi tek başına veya immünsüpresif ajanlarla kombine (CsA, mikofenolat mofetil, azotiopürin, takrolimus, siklofosfamid vb.) kullanılmaktadır (3,5,7).…”

Section: Yöntemlerunclassified

“…), obezite, orak hücreli anemi, renal displazi, HİV, parvovirüs B19, genetik faktörler (NPH1, NPH2, R229Q, CD2AP, α aktinin-4, transiyent reseptör potansiyel katyon kanal mutasyonu vb.) gibi sekonder nedenlere bağlı da gelişebilir (3). FSGS klasik (başka türlü sınıflandırılamayan), selüler, tip varyant, kollapsing varyant ve perihiler olmak üzere histopatolojik olarak beş alt gruba ayrılır (4).…”

Section: Introductionunclassified

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Focal Segmental Glomerulosclerosis: A Single Center Experience

Ayar¹,

Yıldız²,

Oruç³

et al. 2016

Haseki

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

Dan Hu,

Wang,

Liu

et al. 2023

Advanced Science

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

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Glomerular Diseases

Cited by 71 publications

References 53 publications

α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes

α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes

Focal Segmental Glomerulosclerosis: A Single Center Experience

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

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