Biology subjects

Ghanem, S. S.

Publications and source records attributed to Ghanem, S. S..

2 recordsLinked to original sources

bioRxiv2025

Defective insulin clearance plays a primary role in the pathogenesis of chronic kidney disease in mice with null deletion of Ceacam2 gene

Endogenous insulin clearance occurs primarily in hepatocytes and to a lower extent in kidneys proximal tubule cells (KPTCs). CEACAM1 promotes receptor-mediated insulin uptake to be degraded in hepatocytes in a phosphorylation-dependent manner. Its deletion/inactivation causes hyperinsulinemia-driven insulin resistance, steatohepatitis and liver fibrosis. CEACAM2, the dominant CEACAM protein in murine KPTCs, shares a high homology with CEACAM1. Thus, we examined whether it regulates renal insulin disposal to maintain renal homeostasis. KPTCs derived from Ceacam2 null mice (Cc2-/-) exhibited lower receptor-mediated insulin uptake. Combined with the gradual decline in CEACAM1-dependent hepatic insulin clearance, impaired renal insulin clearance contributed to chronic hyperinsulinemia and insulin resistance starting at 10 months of age in Cc2-/-males. This was followed by proteinuria and reduced glomerular filtration rate in association with glomerulosclerosis and tubulointerstitial damage. Increased collagen deposition in Cc2-/- kidneys could be mediated in part, by hyperinsulinemia-driven activation of the 5{beta}1 integrin-focal adhesion kinase (FAK) signaling pathways. Together, the data demonstrated that loss of CEACAM2 impaired renal insulin clearance that contributed to hyperinsulinemia and resultant insulin resistance, followed by kidney dysfunction and renal fibrosis. This study provided an in vivo demonstration of the regulation of kidney function by insulin clearance along the liver-kidney axis.

physiology↗

bioRxiv2021

Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein -synuclein aggregates into Lewy bodies. To explore whether -synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to -synuclein localisation and expression of modifications associated with LBD. To determine whether -synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of -synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived -synuclein. These observations constitute the first report of prion-like -synuclein in the brain tissue of infants and challenge the putative view that -synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

pathology↗