Biology subjects

Kerckhofs, G.

Publications and source records attributed to Kerckhofs, G..

4 recordsLinked to original sources

bioRxiv2024

Pathophysiological response in experimental trauma-related acute kidney injury

BackgroundTrauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes. MethodsTo study the pathophysiology of TRAKI, we developed a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage that induces mild transient TRAKI. ResultsThe mice showed early and transient increased plasma creatinine, urea, NGAL, and urine albumin, resolving 5 days after TRAKI induction. Despite normal kidney morphology, significant damage to proximal tubular cells and a loss of the brush border was observed. This included kidney stress responses, e.g., with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes after trauma. 3D x-ray-based whole-organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood flow, especially during the first day post THS, which was partly resolved by day 5. ConclusionsOur novel model of murine TRAKI has revealed previously unknown aspects of the complex temporal pathophysiological response of the kidney along the nephron after trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches.

pathology↗

bioRxiv2023

Sodium myo-inositol cotransporter-1, SMIT1, promotes cardiac hypertrophy and fibrosis in pressure overloaded mouse hearts

AimsRecent clinical studies have reported that myo-inositol is consistently elevated in plasma of patients with heart failure (HF), yet its role in cardiac dysfunction remains poorly understood. Myo-inositol is specifically transported into cells by the sodium-myo-inositol co-transporter-1 (SMIT1), a member of the sodium-glucose co-transporter (SGLT) family expressed in the heart. While myo-inositol is essential for phosphoinositide signaling, osmoregulation, and metabolic homeostasis, dysregulation of SMIT1-mediated myo-inositol transport may contribute to key pathological mechanisms in HF. This study aims to elucidate the role of SMIT1 in the failing heart, especially during left ventricular remodeling that precedes it. Methods and resultsWe used a mouse model of pressure overload induced by transverse aortic constriction in wild-type (WT) mice and mice lacking SMIT1 (Smit1-/-), and primary cultured cardiomyocytes. By combining molecular, structural and functional studies, RNA-sequencing, and calcium measurements, we demonstrate the contribution of myo-inositol and SMIT1 to pathological hypertrophy and the progression towards HF. We found that in comparison to WT controls, Smit1-/- mice were protected against aortic banding induced systolic dysfunction, cardiac fibrosis and hypertrophy. This hypertrophic response was driven by SMIT1 expression in cardiomyocytes, where it favors intracellular myo-inositol and Na+ entry, leading to inositol 1,4,5-trisphosphate (IP3)- and Ca2+-dependent pro-hypertrophic signaling. Following hemodynamic stress, deletion of SMIT1 significantly altered IP3/calcium effectors, including Carabin, which modulates cardiac hypertrophy through inhibition of the calcineurin/NFAT and Ras/ERK1/2 pathways. ConclusionsThis work provides important insights into the role of myo-inositol and SMIT1 in cardiomyocytes. We demonstrate that SMIT1 is a key driver of pathological hypertrophy by inducing an IP3/Ca2+-dependent pro-hypertrophic transcriptional reprogramming in cardiomyocytes. These findings identify SMIT1 as a promising therapeutic target for preventing or treating pathological cardiac hypertrophy and HF.

cell biology↗

bioRxiv2023

Endothelial SMAD1/5 signaling couples angiogenesis to osteogenesis during long bone growth

Skeletal development depends on coordinated angiogenesis and osteogenesis. Bone morphogenetic proteins direct bone development by activating SMAD1/5 signaling in osteoblasts. However, the role of SMAD1/5 in skeletal endothelium is unknown. Here, we found that endothelial cell-conditional SMAD1/5 depletion in juvenile mice caused metaphyseal and diaphyseal hypervascularity, resulting in altered cancellous and cortical bone formation. SMAD1/5 depletion induced excessive sprouting, disrupting the columnar structure of the metaphyseal vessels and impaired anastomotic loop morphogenesis at the chondro-osseous junction. Endothelial SMAD1/5 depletion impaired growth plate resorption and, upon long term depletion, abrogated osteoprogenitor recruitment to the primary spongiosa. Finally, in the diaphysis, endothelial SMAD1/5 activity was necessary to maintain the sinusoidal phenotype, with SMAD1/5 depletion inducing formation of large vascular loops, featuring elevated endomucin expression, ectopic tip cell formation, and hyperpermeability. Together, endothelial SMAD1/5 activity sustains skeletal vascular morphogenesis and function and coordinates growth plate remodeling and osteoprogenitor recruitment dynamics during bone growth.

developmental biology↗

bioRxiv2019

Ischemic Stroke Reduces Bone Perfusion and Alters Osteovascular Structure

RationaleStroke patients lose bone mass and experience fracture at an elevated rate. Although functional intraosseous vasculature is necessary for skeletal maintenance, the effect of stroke on osteovasculature is unknown.\n\nObjectiveTo characterize changes to osteovascular function, structure, and composition following mild-to-moderate-severity ischemic stroke in mice, both with and without exercise therapy.\n\nMethods and ResultsTwelve-week-old male mice (n=27) received either a stroke (middle cerebral artery occlusion) or sham procedure, followed by four weeks of daily treadmill or sedentary activity. Intraosseous perfusion, measured weekly in the proximal tibial metaphysis, was reduced by stroke for two weeks. In the second week of recovery, exercise nearly restored perfusion to sham levels, and perfusion tended to be lower in the stroke-affected limb. At the conclusion of the study, osteovascular structure was assessed with contrast-enhanced computed tomography in the distal femoral metaphysis. Stroke significantly increased osteovascular volume and branching but reduced the relative number of blood vessels close to bone surfaces (6-22 {micro}m away) and increased the relative number more than 52 {micro}m away. These differences in vessel proximity to bone were driven by changes in the stroke-exercise group, indicating compounded effects of stroke and exercise. Exercise, but not stroke, nearly reduced the amount of osteogenic Type H blood vessels in the proximal tibial metaphysis, quantified with immunofluorescence microscopy.\n\nConclusionsThis study is the first to examine the effects of stroke on osteovasculature. Stroke increased the amount of osteovasculature, but since blood vessels close to bone are associated with bone remodeling, the shift in osteovascular structure could play a role in bone loss following stroke. The exercise-induced reduction in the amount of Type H vessels and the stroke-exercise effect on osteovascular structure suggest moderate aerobic activity may have detrimental effects on bone remodeling during early stroke recovery.

bioengineering↗