bims-raghud 2026-07-26 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–07–26
seven papers selected by
Irene Sambri, TIGEM

mTORC1 activation induces B7-H3-dependent metabolic reprogramming in renal cell carcinoma (RCC).
Down-Regulation of TFEB With Defective Autophagy in the Susceptibility of Aging Kidneys to Septic Acute Kidney Injury.
Kidney organoids as models for hereditary kidney diseases: Toward precision medicine (Review).
Cardiorenal Syndrome: Pathophysiological Crosstalk Between Heart and Kidney.
SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes.
Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
Dapagliflozin modulates diabetic kidney disease through indirect transcriptional regulation rather than direct transcriptional reversal.

Oncogene. 2026 Jul 20.

mTORC1 activation induces B7-H3-dependent metabolic reprogramming in renal cell carcinoma (RCC).

Keying Li, Heng Du, Yifan Wang, Damir Khabibullin, Michel Alchoueiry, Melissa Daou, John M Asara, David J Kwiatkowski, Elizabeth P Henske, Heng-Jia Liu.

Renal cell carcinoma (RCC) affects over 435,000 people worldwide each year and remains a significant cause of cancer mortality. Aberrant activation of pathways such as mTORC1 is frequently observed in RCC, yet the mechanisms by which mTORC1 contributes to tumor development remain poorly understood. The lack of suitable animal models has limited progress in uncovering these mechanisms and advancing targeted treatments. Here, we performed single-cell transcriptomic, proteomic, and metabolomic profiling of kidneys from mice with embryonic Tsc2 deletion at E17.5, which revealed a distinct tumor cell population characterized by intercalated cell signatures, co-expression of Foxi1 and Rhcg, and hyperactivated mTORC1. These lesions closely resemble human chromophobe renal cell carcinoma (ChRCC), a subtype of RCC. The tumors show marked upregulation of the immune checkpoint molecule B7-H3. Mechanistically, the transcription factor NRF1 is elevated in Tsc2-deficient lesions and drives B7-H3 expression in tumor cells. In human specimens, B7-H3 is broadly expressed in both classical and sarcomatoid ChRCC and correlates with hallmark markers FOXI1, MUC2, and HEPACAM2. Strikingly, B7-H3 deletion in mice suppresses Tsc2 loss-driven cystic and tumor formation, restores amino acid metabolism, and attenuates aminoacyl-tRNA biosynthesis and proteasome activity. Collectively, these findings identify B7-H3 as a functional driver of Tsc2-mediated ChRCC and a promising therapeutic target in TSC-associated renal tumors.

DOI: https://doi.org/10.1038/s41388-026-03891-w
Aging Cell. 2026 Aug;25(8): e70644

Down-Regulation of TFEB With Defective Autophagy in the Susceptibility of Aging Kidneys to Septic Acute Kidney Injury.

Yu Xiang, Ying Fu, Zhiwen Liu, Yu Han, Wenwen Wu, Juan Cai, Dongshan Zhang, Zheng Dong.

  Sepsis-associated acute kidney injury (SA-AKI) is a common and devastating disease that has a significantly higher incidence and greater severity in elderly patients, but the molecular basis underlying SA-AKI in the elderly is largely unknown. Recent studies have proved autophagy as an intrinsic protective mechanism against AKI; however, the role and regulation of autophagy in aging kidneys remain unclear. Here we demonstrate that defective autophagy activation in aging kidneys is a key to their susceptibility to SA-AKI. In our experiments, the ability of autophagy activation was impaired in aging kidneys in response to SA-AKI in mice. In vitro, activation of autophagy with TAT-Beclin-1 peptide mitigated lipopolysaccharide (LPS)-induced apoptosis and inflammation in senescent renal proximal tubular cells. Single-cell sequencing revealed significant age-related alterations in autophagy-associated genes in septic AKI, including TFEB. Overexpression of TFEB could partially restore autophagic activity in senescent renal tubular cells and protect them from LPS-induced damage. Moreover, in vivo treatment with the curcumin analog C1 (a TFEB activator) enhanced autophagic function in aging kidneys and reduced LPS-induced AKI. These results demonstrate the defective autophagy activation in aging kidneys, which contributes to the SA-AKI sensitivity and susceptibility in the elderly, suggesting a therapeutic strategy by enhancing autophagy.

Keywords:  TFEB; acute kidney injury; aging; autophagy; sepsis

DOI:  https://doi.org/10.1111/acel.70644
Exp Ther Med. 2026 Sep;32(3): 238

Kidney organoids as models for hereditary kidney diseases: Toward precision medicine (Review).

Sheng Cui, Tianlei Chen, Yun Zou, Min Li, Hua Zhou, Jingting Jiang, Min Yang.

  Kidney organoids are important tools for modeling human development and disease, especially in chronic kidney disease (CKD), which is a global health challenge. Current treatment strategies focus on delaying disease progression by managing underlying causes, and in this regard, kidney organoids offer a platform for mechanism-based therapeutics. Advances in the understanding of human induced pluripotent stem cells (hiPSCs) and sophisticated 3D organ culture methods have enabled researchers to replicate human kidney development and disease mechanisms in vitro, thereby opening new avenues for drug testing. Although the methods for generating renal cell lineages are well established, new protocols for inducing lineages, such as the ureteric bud and collecting ducts, have emerged over the past 5 years. Patient-derived or genetically edited kidney organoids have been used to successfully model various genetic kidney diseases, notably polycystic kidney disease, and to generate kidney tissues that closely mimic the morphology of real organs. However, achieving more complex disease modeling and generating transplantable synthetic kidneys still has notable challenges. The present review discusses the application of hiPSC-derived 3D organoids in CKD research and addresses the limitations of current organ culture methods. The present review also examines the impact of CRISPR/Cas9 technology, and investigates potential future directions.

Keywords:  gene editing; genetic kidney disease; human-induced pluripotent stem cell; kidney organoid

DOI:  https://doi.org/10.3892/etm.2026.13232
Curr Probl Cardiol. 2026 Jul 22. pii: S0146-2806(26)00150-7. [Epub ahead of print] 103408

Cardiorenal Syndrome: Pathophysiological Crosstalk Between Heart and Kidney.

Radhia Chems Telli.

  Cardiorenal syndrome (CRS) describes the bidirectional deterioration of cardiac and renal function, in which dysfunction of one organ induces or perpetuates dysfunction of the other. Since Robert Bright's 1836 observations and the formal five-subtype classification proposed by Ronco and colleagues in 2008, understanding of CRS has evolved from organ-sequential taxonomy toward a mechanism-driven, phenotype-based framework. This narrative review synthesizes contemporary evidence across the molecular, diagnostic, and therapeutic dimensions of CRS. We examine the convergent pathophysiological pathways underlying the syndrome - hemodynamic derangement, renin-angiotensin-aldosterone and sympathetic nervous system activation, systemic inflammation, oxidative stress, mitochondrial and endothelial dysfunction, and the recently characterized gut-heart-kidney axis - with particular emphasis on venous congestion as a unifying mechanistic driver. We review the global epidemiological burden of cardiorenal overlap, now estimated to affect over half of hospitalized heart failure patients, and appraise the diagnostic evolution from creatinine-dependent assessment toward multi-marker biomarker panels and point-of-care venous congestion ultrasonography (VExUS). On the therapeutic front, we highlight the shift toward combination pharmacotherapy - particularly finerenone-SGLT2 inhibitor co-administration - alongside device-based decongestive strategies and early applications of artificial intelligence in cardiorenal phenotyping. We argue that the traditional five-subtype classification, while pedagogically useful, insufficiently captures the overlapping, transitional phenotypes seen in clinical practice, and that congestion-quantified, mechanism-specific management increasingly supersedes rigid subtype-based decision-making. This review concludes by identifying priority areas for future investigation, including randomized congestion-guided decongestion trials and prospective validation of artificial intelligence-derived cardiorenal phenotypes, positioning CRS within the broader emerging construct of cardiovascular-kidney-metabolic syndrome.

Keywords:  Cardiorenal syndrome; SGLT2 inhibitors; biomarkers; chronic kidney disease; finerenone; heart failure; precision medicine; venous congestion

DOI:  https://doi.org/10.1016/j.cpcardiol.2026.103408
Sci Transl Med. 2026 Jul 22. 18(859): eaee1005

SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes.

Petter Bjornstad, Ye Ji Choi, Phoom Narongkiatikhun, Anil Karihaloo, Pottumarthi V Prasad, Lu-Ping Li, Kalie L Tommerdahl, Maninderpal Sethi, Shivani Ramesh, Carissa Birznieks, Antoine Clarke, Yesmino Elia, Jacqueline Curtis, Cheril Clarson, Dylan Weissenkampen, Matteo D'Antonio, Jairo Arturo Pinzon Cortes, Hailey Hampson, Long Yuan, Sarah A van Eeghen, Jenny E Kanter, Karin E Bornfeldt, Tomas Vaisar, Patricia Ladd, Hiddo J L Heerspink, Ian H de Boer, Jesse A Goodrich, Kelly Street, Katherine R Tuttle, Kelly R Bergmann, Cathy Smith, Jeffrey B Hodgin, Jennifer A Schaub, Viji Nair, Rajasree Menon, Abhijit S Naik, Phillip J McCown, Fadhl AlAkwaa, Sean Eddy, Edgar Otto, Nan Hee Kim, Robert G Nelson, Victor G Puelles, Daniël H van Raalte, David Z I Cherney, Laura Pyle, Farid H Mahmud, Matthias Kretzler.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow diabetic kidney disease progression, but their intrarenal mechanisms remain incompletely understood, particularly in type 1 diabetes (T1D), where kidney protection has not been definitively established. ATTEMPT (NCT04333823) was a placebo-controlled trial in which 98 youth (ages 12 to 21) with T1D and hyperfiltration were randomized 1:1 to dapagliflozin (5 milligrams) or placebo for 16 weeks. Participants underwent sequential kidney biopsies, multiparametric kidney MRI, and plasma and urine proteomics. The sequential research kidney biopsies were performed on adults 18 years or older at one of three sites (baseline n = 16, follow-up n = 11). Single-cell RNA sequencing of 214,415 cells across 27 biopsies revealed coordinated transcriptional shifts across nephron, vascular, and immune compartments. In the proximal tubule, the primary site of SGLT2 expression, dapagliflozin down-regulated glycolysis, gluconeogenesis, and oxidative stress markers. Endothelial cells showed reduced profibrotic and inflammatory gene expression with increased protective factors. Podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling. These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation. Trajectory analyses revealed dapagliflozin shifted tubular cells from injury-prone toward healthier phenotypes. Cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. Urine proteomics mirrored tissue changes with decreased injury markers and increased protective proteins. These convergent molecular mechanisms, metabolic reprogramming, dampened inflammation, and normalized oxygen handling provide hypothesis-generating mechanistic insights into potential kidney-protective mechanisms of SGLT2 inhibitor therapy in youth with T1D.

DOI: https://doi.org/10.1126/scitranslmed.aee1005
Nat Cell Biol. 2026 Jul 20.

Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.

Yuanchun Luo, Jianglong Yu, Zhuofan Li, Wanning Li, Le Jiang, Chen Huang, Zhouyi Rong, Long Lin, Yueguang Rong, Chaojun Yan, Zhishui Chen, Jingfeng Tang, He He, Anbing Shi, Zhiyin Song.

Lysosomes are central degradative organelles essential for cellular homeostasis, yet the mechanisms that maintain their integrity and function under stress remain incompletely understood. Here we identify a previously unrecognized lysosomal renewal process, termed budding-type fission (B-fission), which restores lysosomal function during hypoxia-reoxygenation stress. During B-fission, damaged lysosomes generate membrane buds that undergo scission to form small, fully functional lysosomes, independently of autophagic lysosome reformation. Mechanistically, mitochondrial-derived vesicles (MDVs) deliver the fission adaptor MFF to lysosomes, where MFF recruits the dynamin-related GTPase DRP1 to drive membrane scission. MIRO2 promotes the formation of MFF+ MDVs through direct interaction with MFF, while the lysosomal membrane protein ITM2C binds MIRO2 to tether and guide MFF+ MDVs to lysosomes, enabling efficient MFF delivery and subsequent B-fission. Notably, AMPK activation by 991 or metformin promotes MFF-dependent lysosomal B-fission under normoxic conditions, whereas AMPK inhibition by dorsomorphin suppresses B-fission during hypoxia-reoxygenation. This stress-responsive ITM2C-MIRO2-MFF-DRP1 axis co-opts the mitochondrial division machinery to drive lysosomal fission from damaged lysosomes, thereby enabling the undamaged components to reorganize into daughter lysosomes and promote lysosomal renewal. Thus, our findings uncover a fundamental mode of lysosomal renewal and reveal an unexpected role for MDV-mediated mitochondria-lysosome communication in mediating lysosomal quality control during ischaemia-reperfusion and related stresses.

DOI: https://doi.org/10.1038/s41556-026-02010-x
J Nephrol. 2026 Jul 23. pii: aajag074. [Epub ahead of print]

Dapagliflozin modulates diabetic kidney disease through indirect transcriptional regulation rather than direct transcriptional reversal.

Francesco Pesce, Camillo Tancredi Strizzi, Antonio Granata, Maria Elena Bracaccia, Lina Muzi, Vassilios Liakopoulos, Giuseppe Grandaliano.

   BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. While sodium-glucose co-transporter 2 inhibitors (SGLT2i) confer remarkable renoprotection, the molecular mechanisms underlying their efficacy remain incompletely understood.
METHODS: We performed an integrative cross-species transcriptomic analysis comparing dapagliflozin-modulated signatures in diabetic mice with human DKD pathophysiology. Public RNA-sequencing datasets were analyzed: GSE142025 (human kidney biopsies: advanced DKD n = 21, early DKD n = 6, controls n = 9) and GSE228727 (diabetic db/db mice ± dapagliflozin).
RESULTS: Advanced human DKD exhibited 2145 dysregulated genes (False Discovery Rate [FDR] < 0.05) enriched in fibrosis and inflammation pathways. In contrast, dapagliflozin induced a focused 13-gene signature (11 downregulated, 2 upregulated). Matched-cohort analysis revealed minimal overlap between drug and disease signatures: only 7 dapagliflozin-downregulated genes were among diabetes-upregulated genes (hypergeometric P = .542). Gene Set Enrichment Analysis confirmed no global transcriptional reversal (normalized enrichment score [NES] = -1.04, FDR q = 0.86). Despite this limited overlap, unsupervised clustering using the 13-gene signature robustly stratified human patients by disease state.
CONCLUSION: SGLT2 inhibitors do not reverse disease transcriptional programs but operate through indirect modulation of a focused gene signature largely independent of primary disease drivers. This signature provides prioritized candidates for mechanistic investigation and biomarker development in DKD.

Keywords:  SGLT2 inhibitors; dapagliflozin; diabetic kidney disease; gene expression profiling

DOI:  https://doi.org/10.1093/joneph/aajag074