Biology subjects

Thimm, C.

Publications and source records attributed to Thimm, C..

3 recordsLinked to original sources

bioRxiv2023

Cytokines in the Urine of AKI patients regulate TP53 and SIRT1 and can be used as biomarkers for the early detection of AKI

Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication with an incidence of 10-15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. Associated Symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output-although occasionally urine output remains normal, fluid retention-causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, an urgent demand for non-invasive biomarkers for early detection of AKI are highly desirable. This might enable the prevention of the progression from AKI to CKD. In this study, we analysed the secretome of urine of an AKI patient cohort employing a kidney-biomarker cytokine assay. Based on these results we suggest, ADIPOQ, EGF and SERPIN3A as potential biomarkers, which might be able to detect AKI as soon as 24 h post-surgery. For the later stages, common biomarkers for the detection of AKI in both male and female patients we suggest, VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These markers in combination might present a robust strategy to identify the development of AKI as early as 24h or 72h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines in the urine of AKI patients trigger processes which are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest. In conclusion, the Renin-Angiotensin pathway seems to have major implications.

molecular biology↗

bioRxiv2022

Urine-based detection of biomarkers indicative of chronic kidney disease in a patient cohort from Ghana

Chronic kidney disease (CKD) is a global health burden with a continuously increasing prevalence associated with an increasing incidence of diabetes and hypertension in aging populations. The CKD definition of a more than three months lasting low glomerular filtration rate (GFR) or other renal impairments including proteinuria implies that multiple factors may contribute to the disease. While there are indications of ethnic differences it is hard to disentangle these from confounding social factors. Usually, CKD is detected in later stages of the disease when irreversible renal damage has already occurred, thus suggesting a need for early non-invasive diagnostic markers. In this study, we explored the urine secretome of a CKD patient cohort from Ghana employing a kidney-injury and a more general cytokine assay. We identified panels of kidney-specific cytokine markers which were also gender-specific and a panel of gender-independent cytokine markers. The gender-specific markers are IL10 and MME for male and CLU, RETN, AGER, EGFR and VEGFA for female. The gender-independent cytokine markers were APOA1, ANGPT2, C5, CFD, GH1, ICAM1, IGFBP2, IL8, KLK4, MMP9 and SPP1 (up-regulated) and FLT3LG, CSF1, PDGFA, RETN and VEGFA (down-regulated). APOA1 - the major component of HDL particles - was up-regulated in Ghanaian CKD patients and its co-occurrence with APOL1 in a subpopulation of HDL particles may point to specific CKD-predisposing APOL1 haplotypes in patients of African descent - this however needs further investigation. The identified panels may lay down the foundation for CKD-biomarker assays to be confirmed in further studies with a larger cohort of patients.

molecular biology↗

bioRxiv2022

Derivation of the immortalized cell line-UM51-PrePodo-hTERT and its responsiveness to Angiotensin II and activation of RAAS

Recent demographic studies predict there will be a considerable increase of elderly people within the next decades. Aging has been recognized as one of the main risk factors of the worlds most prevalent diseases, including neurodegenerative disorders, cancer, cardiovascular disease, and metabolic disease. During the process of aging a gradual loss of tissue volume and organ function is observed, which is partially caused by replicative senescence. The capacity of cellular proliferation and replicative senescence is tightly regulated by their telomere length. When the telomere length with progressive cell division is critically shortened, the cell becomes proliferative arrested and DNA damage response and cellular senescence are triggered. At this time point the so called "Hayflick limit" is attained. Podocytes are a cell type that is found in the kidney glomerulus where they have major implications in blood filtration. Mature podocytes are terminal differentiated cells that are unable to undergo cell division in vivo. For this reason, the establishment of podocyte cell cultures has been very challenging. In our present study, we present the successful immortalization of a human podocyte progenitor cell line, of which the primary cell cells were isolated directly from the urine of a 51-year-old male. The immortalized cell line has been cultured over the course of one year ([~]100 passages) with high proliferation capacity, while still endowed with contact inhibition and P53 expression and activation. Furthermore, by immunofluorescent-based expression and quantitative Real-Time PCR for the podocyte markers NPHS1, SYNPO and WT1 we confirmed the differentiation capacity of the immortalized cells. Finally, we evaluated and confirmed the responsiveness of the immortalized cells on the main mediator Angiotensin II (ANGII) of the renin-angiotensin-system (RAS). Elevated levels of ANGII have been identified as a main risk factor for the initiation and progression of chronic kidney disease (CKD). CKD is characterized by an impairment of podocyte function and subsequently podocyte apoptosis. As a major risk factor for patients to develop CKD, diabetes, hypertension, heart disease and stroke have been recognized - all of which show increased incidence in elderly people. In conclusion, we have shown that it is possible to by-pass cellular replicative senescence (Hayflicks limit) by TERT-driven immortalization of human urine-derived pre-podocyte cells from a 51-year-old African male.

cell biology↗