Biology subjects

Lamas, S.

Publications and source records attributed to Lamas, S..

6 recordsLinked to original sources

bioRxiv2025

αTAT1 defines a microtubule mechanosensing axis that drives fibroblast durotaxis and fibrosis across organs

Durotaxis, the directed migration of cells along gradients of extracellular stiffness, drives tissue fibrosis by recruiting fibroblasts to stiffened injury sites where hey differentiate into myofibroblasts and deposit scar tissue. While actin cytoskeletal tension and focal adhesion dynamics have been implicated in this process, the contribution of microtubules to cellular mechanosensing and durotaxis has remained undefined. Here, we uncover TAT1-mediated microtubule acetylation as a master regulator of fibroblast mechanosensing and stiffness-directed durotaxis. By catalyzing -tubulin K40 acetylation, TAT1 confers the structural flexibility required for directional microtubule alignment and persistent polarity along stiffness gradients, enabling fibroblasts to sense mechanical cues and initiate profibrotic programs. Loss of TAT1 abolishes K40 acetylation, disrupts focal adhesion FAK signaling, and suppresses YAP nuclear localization, thereby uncoupling extracellular matrix stiffness from downstream mechanotransduction. Global or fibroblast-specific deletion of TAT1 markedly reduces fibroblast durotaxis and myofibroblast accumulation, and protects mice from lung, dermal, and kidney fibrosis in experimental models, without affecting inflammation or vascular integrity. Together, our findings define TAT1-dependent microtubule mechanosensing as a central cytoskeletal pathway coupling fibroblast mechanobiology to organ fibrosis in vivo, positioning the TAT1 catalytic domain as a novel mechano-therapeutic target in fibrotic disease.

cell biology↗

bioRxiv2025

Time-Restricted Feeding Attenuates Kidney Damage and Preserves Renal Function in Mouse Model of Chronic Kidney Disease

Chronic kidney disease (CKD) is a highly disabling and potentially deadly condition for which there is no cure. With renal damage risk factors such as hypertension, metabolic syndrome and type 2 diabetes on the rise, the prevalence of CKD is increasing worldwide. New therapeutic approaches to CKD management are thus warranted. Time-restricted feeding, a dietary intervention in which daily food intake is limited to a consistent time window, has shown benefits in the context of metabolic disease management. Boolean implication network model of human CKD gene expression data and data from mouse TRF kidney implied TRF could attenuate kidney injury from CKD. We tested the effect of TRF in mouse models of kidney damage under high-fat high-sucrose feeding to induce a metabolic-disease prone environment. Using gold standard pre-clinical models of renal fibrosis, we discovered that TRF protected from kidney damage and clinical features of CKD. At the molecular level, the effects of TRF were pleiotropic with benefits in pathways involved in renal inflammation, fibrosis, and ER stress. Importantly, our results also suggest that TRF can confer early protection from metabolic alterations implicated in kidney damage.

pathology↗

bioRxiv2022

Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses

Chronic kidney disease is a highly prevalent condition that remains a major clinical and biomedical challenge. Tubulo-interstitial fibrosis is the common pathological substrate for many causes that lead to chronic kidney disease. It is characterized by profound derangements in metabolic and inflammatory responses, whereby functional tissue is replaced with extracellular matrix, leading to the suppression of renal function. Perturbations in the circadian rhythm have been associated with many human pathologies, including renal disease. However, the role of the molecular clock in the instauration of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (UUO, FAN and adenine toxicity), employing genetically-modified mice with selective deficiencies of the clock components Bmal1, Clock and Cry. We found that UUO induced a marked increase in the expression of Bmal1. In human tubular epithelial cells, the pro-fibrotic mediator, TGF-{beta}, significantly altered the expression of core clock components. We further observed that the absence of Cry drastically aggravated kidney fibrosis, while both Cry and Clock played a role in the neutrophil and macrophage mediated inflammatory response, respectively. Suppression of Cry1/2 was associated with a major shift in the expression of metabolism-related genes, underscoring the importance of metabolic dysfunction in fibrosis. These results support a reciprocal interaction between the circadian clock and the response to kidney injury. Translational statementChronic kidney disease (CKD) is a highly prevalent clinical syndrome that still poses major clinical challenges. Kidney fibrosis underlies many cases of CKD and therapies against it are of very limited efficacy. Alterations in circadian rhythms (CR) are relevant in patients with CKD, but very little is known about the relationship between CKD and CR. Our study shows that disruption of the molecular clock can impact kidney inflammation and fibrosis and that, reciprocally, kidney fibrosis can alter the expression of clock components. A better understanding of this crosstalk could open new therapeutic avenues for the prevention and treatment of CR-related CKD.

physiology↗

bioRxiv2020

Causes of death in newborn C57BL/6J mice

Neonatal mortality in wild-type laboratory mice is an overlooked welfare and financial problem in animal facilities around the world. Causes of death are often not reported and its causes remain unknown. In this study, 324 newborn pups from two breeding colonies of healthy wildtype C57BL/6 mice underwent post-mortem analysis with special focus on obtaining proof of life after birth, evaluation of stomach contents and observation of congenital abnormalities that could compromise survival. Based on a combination of lung morphology findings, outcome of lung float test, stomach contents and brown adipose tissue colouration, 21.6% of the pups found dead were considered stillbirths. Of the livebirths, only 3.2% were observed to have milk inside the stomach, indicating successful suckling. Congenital abnormalities were diagnosed only in a small fraction of the pups analysed. These results suggest that starvation was the most common cause of death, followed by stillbirth.

pathology↗

bioRxiv2020

Renal tubule Cpt1a overexpression mitigates kidney fibrosis by restoring mitochondrial homeostasis

Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-of-function (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients evidenced decreased CPT1 levels and increased accumulation of short and middle chain acyl-carnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD. Graphical abstractOverexpression of CPT1A impedes tubular epithelial renal cell dedifferentiation and a pro-fibrotic phenotype by restoring mitochondrial metabolic bioenergetics. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗

bioRxiv2019

MiR-9-5p protects from kidney fibrosis by metabolic reprogramming

MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and control biological processes, including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-{beta}1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA sequencing (RNA-Seq) studies in the UUO model revealed that this protection was mediated by a global shift in the expression profile of genes related to key metabolic pathways, including mitochondrial dysfunction, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and glycolysis, preventing their UUO-dependent down-regulation. This effect was mirrored by a prevention in the TGF-{beta}1-induced bioenergetics changes in HKC-8 cells. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1)-peroxisome proliferator-activated receptor alpha (PPAR) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.

molecular biology↗