👤 Tatiana N Tarasenko

to evaluate the expression of profibrotic markers TGF-1, MMP-9 and FGFR in the epithelium of proximal renal tubules in patients with urolithiasis depending on the composition of the nodule, as well as on the degree of decrease in the glomerular filtration rate (GFR). complex examination of 17 patients with urolithiasis was carried out. Cockcroft-Gault formula for determining the glomerular filtration rate was used to estimate renal function, according to the results of which all patients were divided into 3 groups depending on the stage of GFR. Percutaneous nephrolithotripsy (PNLT) was performed according to the standard technique using laser treatment. The physical and chemical composition of the nodule was determined by polarization microscopy. All patients underwent morphological and morphometric study of nephrobiopsy specimens obtained at creation of puncture passage during PNLT in patients with nephrolithiasis. Immunohistochemical study was performed using profibrotic marker Anti-TGF beta 1 antibody (1:500, Abcam, UK), Anti-MMP-9 antibody (1:500, Abcam, UK), Anti-FGFR-1 1:50, Abcam, UK). Analysis of the results of morphological study revealed a correlation only between morphological manifestations of CPN progression and expression of profibrotic marker TGF-. The increase in TGF- expression is accompanied by more pronounced atrophic changes in the epithelium of proximal renal tubules, which indicates the triggering of tubulointerstitial fibrosis mechanisms and the role of this marker in the progression of chronic kidney disease in patients with urolithiasis. Show less

The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of inborn errors of metabolism. Show less