ECP 2022 Abstract Book

Virchows Archiv (2022) 481 (Suppl 1):S1–S364 13 regenerative processes characterized by hypertrophy of glomeruli with hyperplasia of capillary loops, activation of proliferative potential of nephrons cells, angiogenesis activation. The latter were more pronounced in kidneys of newborns that developed under maternal IDA conditions. The data obtained by the authors indicate a more pronounced damaging effect on the newborns kidneys of maternal PE compared to IDA. PS-04-006 Renal amyloid deposition limited to glomeruli in caveolin-1 knockout mice G. Terinte-Balcan*, D. Marta, M. Gherghiceanu *"Victor Babes" National Institute of Pathology, Romania Background & objectives: Caveolae are invaginations of the plasma membrane involved in many different disease processes, such as cardiovascular diseases, infections, diabetes, drug sensitiv- ity and cancer. The objective of this study was to assess the renal pathological abnormalities in cav-1 knockout ageing mice. Methods: Renal tissue from 6 and 18 month-old cav-1 knockout mice was processed for paraffin and plastic embedding in order to be examined using light microscopy (LM) and electron microscopy (EM). Slides with paraffin embedded tissue were processed for immunofluorescence microscopy (IF) and examined using the fol- lowing markers: IgA, IgM, IgG, C3, C1q, fibrin, kappa and lambda light chains. Results: LM showed normal structure of kidney from 6 month- old mice and large amorphous deposits located only in the glomeruli from 18 month-old mice. There was no endocapillary hypercellularity, fibrinoid necrosis or crescents in the glomeruli. The tubulo-interstitial and vascular compartments of the kidney had a normal structure. IF was negative in the glomeruli and there were no extraglomerular deposits on any marker examined. EM showed non-branching, randomly arranged fibrils, with a diameter between and 7 and 12 nm located only in the glomeruli. Based on the findings observed by LM, IF and EM, a diagnosis of amyloidosis limited to the glomeruli in the kidneys of aged mice was made. Conclusion: There are several experiments in animal models and HEK cells that demonstrate a connection between cav-1 levels and amyloid precursor proteins. In humans, variations in the CAV1 gene have been reported in association with metabolic disorders and cardiovascular disease. This study represents the first report of amyloid deposition in the kidneys of cav-1 knockout aged mice, further strengthening the evidence that cav-1 and caveolae are implicated in disease pathophysiology. PS-04-007 Clinical and pathohistological characteristics of COL4A3 c.2881+1G>A variant causing Alport spectrum disorders in Croatian population M. Horaček*, P. Šenjug, S. Kuzmac, M. Šenjug Perica, D. Klarić, F. Paić, T. Nikuševa Martić, D. Galešić Ljubanović *Institute of Pathology, School of Medicine, University of Zagreb, Croatia Background & objectives: Alport syndrome (AS) and thin base- ment membrane nephropathy (TBMN) are kidney disorders caused by mutations in COL4A3, COL4A4, or COL4A5 genes that encode polypeptide chains of collagen IV, the major structural component of basement membranes. Methods: We identified 13 patients from 12 unrelated families with a pathohistological diagnosis of AS or TBMN who tested positive for a heterozygous variant COL4A3 c.2881+1G>A on conducted next-generation sequencing (NGS). Subsequently, their family members were recruited for genetic counselling, urinalysis, and blood sampling for targeted NGS. A correlation of clinical and pathohistological data and genealogy study was also performed. Results: Overall, 34 patients (58.8% male) were found positive for heterozygous, disease-causing variant COL4A3 c.2881+1G>A. Haematuria was present in 33 patients (97.1%), while 19 (55.9%) had proteinuria. Follow-up data showed that four more patients developed proteinuria (23 total; 67.6%) and 6 (17.6%) developed chronic kidney disease, started dialysis or underwent kidney trans- plantation by the median age of 51 years. There were 6 (17.6%) patients with hearing loss (3 confirmed with audiogram) and 4 (11.8%) with ocular lesions. Among 13 patients who underwent kidney biopsy, 12 had glomeruli available for electron microscopy. Five patients had classic AS morphology and 7 had TBMN (3 of them with focal lamellation). Conclusion: The suspected founder var iant COL4A3 c.2881+1G>A is disease-causing. There is variability among these patients not only in clinical presentation but also in pathohistologi- cal findings. Interestingly five out 12 heterozygous patients had classic AS morphology on kidney biopsy. It is essential to conduct a detailed analysis of each collagen IV variant to optimize the affected patients’ prognostic and therapeutic approach. PS-04-008 Ursolic acid prevents the dysregulation in the expression of his- tone methylation-related epigenetic enzymes in diabetic kidney S. Manea*, A. Lazar, M.L. Vlad, A. Manea *Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, Romania Background & objectives: Histone methyltransferases (KMTs)/ demethylases (KDMs) play a major role in the pathology of diabetic kidney disease (DKD). We aimed at investigating the potential role of ursolic acid (UA), a pentacyclic triterpenoid, to modulate the expression of archetypal KMTs/KDMs in diabetic kidney. Methods: Non-diabetic and streptozotocin-induced diabetic C57BL/6J mice were randomized to receive via intraperitoneal injection 1 mg/kg UA, or its vehicle for 4 weeks. Human endothelial cells (EA.hy926) were exposed to normal (5 mM) or high (25 mM) concentrations of glucose in the absence/presence of UA (5 μM). Hematoxylin-eosin staining, fluorescence microscopy, real-time PCR and Western blot were employed. Results: No significant changes in blood glucose levels and body weights were detected following UA administration to diabetic mice as compared with vehicle-treated diabetic animals. Glomerular hypertrophy and enhanced accumulation of extracellular matrix proteins were detected in diabetic kidney. The mRNA and protein levels of KMT (DOT1L, SETD7, EHMT1, EHMT2, EZH1, EZH2) and KDM (KDM1A, KDM2A, KDM3A, KDM4A, KDM5A, KDM5B) subtypes were found significantly elevated in the kidney of diabetic mice as compared with non-diabetic animals. Treatment of diabetic mice with UA suppressed the up-regulation of KMTs and KDMs. High glucose-induced increased expression of the archetypal KMT and KDM subtypes was significantly reduced by UA in cultured endothelial cells. Conclusion: Selective triterpenic acids are generally acknowl- edged as potential medicines for the treatment of a wide range of human pathologies. In this study, we provide evidence that ursolic acid prevents the alterations in gene and protein expression levels of archetypal KMTs and KDMs in the kidney of diabetic mice. Ursolic acid or its pharmacologically active chemical derivates may become important therapeutic tools to prevent epigenetic S86