Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury
| Main Author: | |
|---|---|
| Language: | English |
| Published: |
University of Cincinnati / OhioLINK
2021
|
| Subjects: | |
| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623250686588821 |
| id |
ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1623250686588821 |
|---|---|
| record_format |
oai_dc |
| spelling |
ndltd-OhioLink-oai-etd.ohiolink.edu-ucin16232506865888212021-10-06T05:10:48Z Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury Rudomanova, Valeriia Molecular Biology AKI CKD single cell RNA-seq renal myofibroblast Sox4 cell-to-cell crosstalk Acute kidney injury (AKI) is a rapid renal function decline, with an intensive care unit incidence of up to 67% and merely supportive treatments. This functional deterioration is due to several underlying pathologic processes including pro-fibrotic and pro- inflammatory phenotypic changes and death of the renal tubular cells which are responsible for crucial kidney functions. Furthermore, repetitive insults and maladaptive injury response could lead to the replacement of functional renal parenchyma with fibrotic tissue, which constitutes the pathogenesis of chronic kidney disease (CKD). CKD is a debilitating condition requiring life-time therapeutic maintenance and dialysis support or renal replacement therapy. Thus, there is a need for deeper understanding of the molecular genetics and mechanisms of early AKI since identification of the molecular factors responsible for kidney recovery versus maladaptive injury response could lead to improved preventative treatment. Moreover, examining the long-term renal injury could reveal the molecular and cellular mechanisms of renal fibrotic remodeling, particularly the molecular identity of renal fibroblasts, which would allow for targeted CKD therapy.In recent years, significant progress had been made in kidney injury research. Particularly, single cell RNA sequencing (scRNA-seq) substantially improved our understanding of the genetics and cellular composition of the developing, adult and diseased kidney. However, a thorough atlas of progressive gene expression changes induced by AKI is paramount for understanding of the molecular nature of kidney injury response. In Chapter 2, we present the comprehensive renal cell type specific transcriptional profiles of multiple murine AKI stages created using scRNA-seq and validated with single molecule in situ hybridizations, protein expression and human tissue analyses. We revealed that the injured renal tubules exhibit profound pro-inflammatory and pro-fibrotic phenotype and significant nephrogenic signature represented by renal developmental genes Sox4 and Cd24a. Moreover, we identified several novel genes upregulated in the injured tubules (Ahnak, Myh9, Sh3bgrl3, Col18a1) along with the potential pathologic epithelial-to-stromal crosstalk. Our work also demonstrated that advancing AKI onset age results in maladaptive response and kidney fibrosis.In Chapter 3, we examined single cell specific transcriptional changes in two clinically relevant CKD murine models, aiming to reveal the transcriptional identity of the cells involved in the renal fibrotic remodeling. Using two different scRNA-seq platforms, we identified three distinctive renal fibroblast populations and persistent epithelial-to-stromal crosstalk, which corroborates the role of tubular epithelial cells in renal fibrosis induction. Moreover, we mechanistically examined the role of several novel genes identified by our AKI and CKD studies and demonstrated that Ahnak, Myh9 and Col18a1 knockouts alter the TGFß response in the primary human proximal tubular cells in vitro. Collectively, our work elucidated several novel molecular factors, mechanisms and cell populations involved in kidney injury progression, and provided a valuable resource for the field to examine the molecular genetics of AKI and CKD. 2021-10-05 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623250686588821 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623250686588821 restricted--full text unavailable until 2023-08-09 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Molecular Biology AKI CKD single cell RNA-seq renal myofibroblast Sox4 cell-to-cell crosstalk |
| spellingShingle |
Molecular Biology AKI CKD single cell RNA-seq renal myofibroblast Sox4 cell-to-cell crosstalk Rudomanova, Valeriia Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury |
| author |
Rudomanova, Valeriia |
| author_facet |
Rudomanova, Valeriia |
| author_sort |
Rudomanova, Valeriia |
| title |
Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury |
| title_short |
Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury |
| title_full |
Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury |
| title_fullStr |
Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury |
| title_full_unstemmed |
Unraveling the Secrets of Kidney Disease: Novel Molecular Mechanisms of Acute and Chronic Kidney Injury |
| title_sort |
unraveling the secrets of kidney disease: novel molecular mechanisms of acute and chronic kidney injury |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2021 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623250686588821 |
| work_keys_str_mv |
AT rudomanovavaleriia unravelingthesecretsofkidneydiseasenovelmolecularmechanismsofacuteandchronickidneyinjury |
| _version_ |
1719487309532889088 |