Cellular and molecular mechanisms of kidney injury and regeneration
Abstract
The prevalence of kidney disease is constantly increasing with about 600 million people afflicted globally. Kidney disease may result in end stage renal disease, a condition that requires renal replacement therapy in the form of kidney transplantation or dialysis. However, the mechanisms behind kidney injury and regeneration are still incompletely understood. In this thesis, we aimed to study the phenotype of the scattered tubular cells (STCs), a cell population distributed throughout the proximal tubules (PT) of human kidney involved in injury and regeneration, for better understanding of the underlying mechanisms of tubular repair. In Paper I, we established SOX9 as an STC marker and demonstrated that SOX9 is activated in response to injury in the human kidney. Furthermore, we identified LBR, HMGA2, and HIPK3 as potential downstream targets of SOX9 in tubular repair. In Paper II, we observed that the STC phenotype is induced in cultured primary PT cells and that the PT phenotype could be partially restored by re-expression of HNF4A. In Paper III, we showed that the STCs have a general reduction of mitochondrial markers, and we also found another cell population in the PT which displayed selective loss of mitochondrial respiratory chain complex I that increased with age. In Paper IV, we presented ARMH4 and WIPF3 as novel podocyte proteins possibly involved in glomerular injury and disease. Taken together, these findings elucidate potential therapeutic targets during kidney injury and regeneration.
Parts of work
I. Kha M, Krawczyk K, Choong OK, De Luca F, Altiparmak G, Källberg E, Nilsson H, Leandersson K, Swärd K, Johansson ME. The injury-induced transcription factor SOX9 alters the expression of LBR, HMGA2, and HIPK3 in the human kidney. Am J Physiol Renal Physiol. 2023;324(1):F75-F90. https://doi.org/10.1152/ajprenal.00196.2022 II. Kha M, Altiparmak G, Lundgren J, Swärd K, Johansson ME. HNF4A re-expression partially restores a proximal tubular phenotype in cultured primary kidney cells. Manuscript III. Kha M, Altiparmak G, Elliott K, Xie X, Larsson E, Oldfors A, Swärd K, Johansson ME. Age and injury-related changes of mitochondrial respiratory complexes in human kidney tubules. Manuscript IV. De Luca F, Kha M, Swärd K, Johansson ME. Identification of ARMH4 and WIPF3 as human podocyte proteins with potential roles in immunomodulation and cytoskeletal dynamics. PLoS One. 2023;18(1):e0280270. https://doi.org/10.1371/journal.pone.0280270
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Biomedicine. Department of Laboratory Medicine
Disputation
Fredagen den 8 december 2023, kl. 9.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg.
https://gu-se.zoom.us/j/68113474947?pwd=MCsvQWlJQjdJbTVzem5pTmw2NVYxUT09
Date of defence
2023-12-08
michelle.kha@gu.se
Date
2023-11-13Author
Kha, Michelle
Keywords
kidney
injury
regeneration
repair
scattered tubular cells
proximal tubular cells
podocytes
SOX9
HNF4A
Publication type
Doctoral thesis
ISBN
978-91-8069-417-9 (PRINT)
978-91-8069-418-6 (PDF)
Language
eng