Baber, R. | bioRxiv Science

bioRxiv2025

Retinal nerve fibre layer thickness reflects characteristics of brain grey and white matter

The retina is a relatively accessible part of the central nervous system compared to the brain. Using high resolution optical imaging we investigated the relationship between retinal thickness, obtained with optical coherence tomography, and structural features of the brain obtained with magnetic resonance imaging. In a population-based sample of over 500 subjects, we hypothesized: (i) that there are structural associations between circumpapillary retinal nerve fibre layer thickness and brain grey matter density and white matter microstructural properties in visual information processing areas, and specifically contralateral associations for nasal retinal fibers, and (ii) that retinal findings reflect broader changes in brain grey and white matter related to cardiovascular risk factors. In support of the first hypothesis, we showed associations of circumpapillary retinal nerve fibre layer thickness with visual cortex grey matter density and with optic radiation fractional anisotropy. These correlations were stronger for the right eye, possibly reflecting right ocular dominancy. Regarding the second hypothesis, while we confirmed the broad impact of cardiovascular risk factors such as body mass index, diabetes, and hypertension on brain structure, we didnt find (adequate) significant partial correlations between circumpapillary retinal nerve fibre layer thickness and cardiovascular risk factors to support the hypothesis. As such, we couldnt confirm that circumpapillary retinal nerve fibre layer thickness is associated with the impact of cardiovascular risk factors on the brain structure. However, when the effects of cardiovascular risk factors were accounted for statistically, circumpapillary retinal nerve fibre layer thickness (particularly on the right side) was associated with fractional anisotropy of limbic system tracts, i.e., the fornix and stria terminalis including hippocampus and amygdala. To further explore the structural associations between eye and brain, in terms of a possible common underlying pathology related to cardiovascular risk factors and progressive neurodegenerative diseases on the central nervous system, longitudinal and interventional studies are necessary.

neuroscience↗

bioRxiv2021

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

A major therapeutic obstacle in diabetes mellitus is the metabolic or hyperglycemic memory: the persistence of impaired organ function despite improvement of blood glucose. Therapies reversing the hyperglycemic memory and thus improving already established organ-dysfunction are lacking, but urgently needed considering the increasing prevalence of diabetes mellitus worldwide. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with sustained induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, in several independent human samples and in in vitro models. Tubular p21 expression and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans, suggesting that p21 may be a biomarker indicating persistent ("memorized") kidney damage. Glucose-mediated p21 induction and tubular senescence were enhanced in mice with reduced levels of the disease resolving protease activated protein C (aPC). Mechanistically, glucose-induced and sustained tubular p21 expression is linked with demethylation of its promoter and reduced DNMT1 expression. aPC reverses already established p21 expression independent of its anticoagulant function through receptor signaling. Accordingly, new pharmacological approaches specifically mimicking aPC signaling (3K3A-aPC, parmodulin-2) enabled the reversal of glucose-mediated sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence contributes to the hyperglycemic memory but can be therapeutically targeted. Single sentence summaryaPC signaling targets persistent p21 expression and tubular senescence and reverses the hyperglycemic memory in diabetic kidney disease.

molecular biology↗