bims-raghud 2025-05-25 papers

Eur Urol. 2025 May 16. pii: S0302-2838(25)00281-7. [Epub ahead of print]

Circ Res. 2025 May 23. 136(11): 1476-1493

In Vitro Modeling of Interorgan Crosstalk: Multi-Organ-on-a-Chip for Studying Cardiovascular-Kidney-Metabolic Syndrome.

Cody Juguilon, Ramak Khosravi, Milica Radisic, Joseph C Wu.

Cardiovascular-kidney-metabolic syndrome is a progressive disorder driven by perturbed interorgan crosstalk among adipose, liver, kidney, and heart, leading to multiorgan dysfunction. Capturing the complexity of human cardiovascular-kidney-metabolic syndrome pathophysiology using conventional models has been challenging. Multi-organ-on-a-chip platforms offer a versatile means to study underlying interorgan signaling at different stages of cardiovascular-kidney-metabolic syndrome and bolster clinical translation.

Keywords: ; cardiovascular diseases; heart failure; inflammation; kidney; metabolic syndrome

DOI: https://doi.org/10.1161/CIRCRESAHA.125.325497

JCI Insight. 2025 May 20. pii: e172370. [Epub ahead of print]

Loss of genome maintenance is linked to mTORC1 signaling and accelerates podocyte damage.

DNA repair is essential for preserving genome integrity. Podocytes, post-mitotic epithelial cells of the kidney filtration unit, bear limited regenerative capacity, yet their survival is indispensable for kidney health. Podocyte loss is a hallmark of the aging process and of many diseases, but the underlying factors remain unclear. We investigated the consequences of DNA damage in a podocyte-specific knockout mouse model for Ercc1 and in cultured podocytes under genomic stress. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages and patients suffering from minimal change disease and focal segmental glomerulosclerosis. Ercc1 knockout resulted in accumulation of DNA damage, ensuing albuminuria and kidney disease. Podocytes reacted to genomic stress by activating mTORC1 signaling in vitro and in vivo. This was abrogated by inhibiting DNA damage signaling through DNA-PK and ATM kinases and inhibition of mTORC1 modulated the development of glomerulosclerosis. Perturbed DNA repair gene expression and genomic stress in podocytes was also detected in focal segmental glomerulosclerosis. Beyond that, DNA damage signaling occurred in podocytes of healthy aging mice and humans. We provide evidence that genome maintenance in podocytes is linked to the mTORC1 pathway, involved in the aging process and the development of glomerulosclerosis.

Keywords: Aging; Cell biology; Chronic kidney disease; DNA repair; Nephrology

DOI: https://doi.org/10.1172/jci.insight.172370

Cancer Lett. 2025 May 15. pii: S0304-3835(25)00373-8. [Epub ahead of print]625 217806

YAP/TAZ: An epitome of tumorigenesis.

Soumya Mukherjee, Emily A Warden, Jianmin Zhang.

Mounting evidence has demonstrated that the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are the main effectors of the Hippo signal transduction pathway that is involved in multiple layered events in tumorigenesis. The role of YAP/TAZ in cancer development is critical in a context dependent manner. Overexpression of YAP/TAZ induces cell proliferation and is elevated in various cancers and many other malignancies. On the other hand, studies have shown YAP binds p73 to activate PML transcription in response to DNA damage and generate a DNA-damage-induced feedback loop. Intriguingly, at the genomic level, YAP/TAZ genes are rarely mutated in cancer, except in specific tumors. The central role of YAP/TAZ in driving tumorigenesis is attributed through diverse mechanisms, such as regulatory kinases, cellular mechano-transduction, epigenetic modification/alterations, post-translational modifications, protein -protein interaction and nucleo-cytoplasmic export import. The complex interplay among feedback loops and crosstalk between various signaling pathways portrays the dynamic nature of YAP/TAZ. Thus, a comprehensive understanding of how posttranslational modifications and nucleo-cytoplasmic traffic of YAP/TAZ dynamically regulate and control each other holds great promise for selectively targeting YAP/TAZ import and export for drug therapy.

Keywords: Hippo pathway; Post translational modifications (PTM); Transcriptional coactivator with PDZ-Binding motif (TAZ); Tumorigenesis; Yes-associated protein (YAP)

DOI: https://doi.org/10.1016/j.canlet.2025.217806

Hum Pathol. 2025 May 17. pii: S0046-8177(25)00086-3. [Epub ahead of print]159 105799

Unlocking diagnostic potential: A retrospective analysis of GPNMB immunohistochemistry in nearly 1000 surgical pathology specimens.

Huili Li, Andres Matoso.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a lysosomal transmembrane protein regulated by the TSC/mTOR-TFE pathway and has been proposed as a diagnostic immunohistochemical (IHC) marker for tumors associated with TSC/mTOR-TFE pathway alterations. However, its diagnostic performance in routine surgical pathology has not been systematically evaluated on a large scale. We retrospectively reviewed 934 cases from the Johns Hopkins pathology archives (2021-2025) in which GPNMB IHC was performed. Diagnoses were categorized into TSC/mTOR-TFE-related, non-TSC/mTOR/TFE-related, or undefined molecular groups. Correlation with fluorescence in situ hybridization (FISH) results and histologic features was performed to assess diagnostic utility. GPNMB was diffusely positive in 94.8 % (218/230) of TSC/mTOR-TFE-related neoplasms, including renal cell carcinomas with TFE3/TFEB rearrangements, perivascular epithelioid cell tumors (PECOMA/AML), and other related entities. In contrast, 83.3 % of non-TSC/mTOR-TFE-related tumors were negative for GPNMB. Discordant cases were seen in both groups, likely reflecting molecular heterogeneity, limitations of FISH, or the complex regulation of GPNMB expression. GPNMB outperformed cathepsin K in sensitivity in FISH-confirmed cases with TFE3 or TFEB alterations. Patchy or equivocal staining required careful histologic and ancillary correlation for interpretation. GPNMB IHC is a valuable ancillary tool in diagnosing TSC/mTOR-TFE-related neoplasms, particularly in renal and mesenchymal tumors. While not perfectly specific or sensitive, it offers a rapid and cost-effective alternative to molecular testing and can guide further diagnostic workup. Positive GPNMB staining in tumors without known TSC/mTOR-TFE alterations may suggest secondary pathway involvement, warranting additional molecular studies.

Keywords: Angiomyolipoma; GPNMB; PECOMA; Renal neoplasm; TFE3; TFEB; TSC; mTOR

DOI: https://doi.org/10.1016/j.humpath.2025.105799

MicroPubl Biol. 2025 ;2025

Hyperactivation of mTORC1 by an endogenous raga-1 gain-of-function mutation does not reduce lifespan in C. elegans.

Tatiana M Moreno, Michelle E Brown, Caroline Kumsta.

Inhibition of mTORC1, a conserved nutrient-sensing complex, extends lifespan across model organisms, but the effects of mTORC1 hyperactivation are less understood. RagA, a GTPase essential for mTORC1 activation, can be locked in its active GTP-bound state through gain-of-function mutations, such as Q63L in C. elegans RAGA-1. We found that transgenic expression of raga-1[Q63L] mutation ( egIs12 ) decreases lifespan without hyperactivating mTORC1, suggesting mTORC1-independent effects or transgene toxicity. In contrast, we show that a CRISPR-generated Q63L mutation at the endogenous raga-1 locus ( viz128) hyperactivates mTORC1 without affecting lifespan, challenging the paradigm that mTORC1 hyperactivation accelerates aging. Thus, genetic context and potential compensatory mechanisms may contribute to mTORC1-mediated lifespan regulation, at least in metazoans.

DOI: https://doi.org/10.17912/micropub.biology.001520