The role of Crim1 in obstructive nephropathy and progressive renal fibrosis in the Crim1KST264/KST264 mice

Phua, Yu Leng (2013). The role of Crim1 in obstructive nephropathy and progressive renal fibrosis in the Crim1KST264/KST264 mice PhD Thesis, Institute for Molecular Bioscience, The University of Queensland.

       
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Author Phua, Yu Leng
Thesis Title The role of Crim1 in obstructive nephropathy and progressive renal fibrosis in the Crim1KST264/KST264 mice
Formatted title
The role of Crim1 in obstructive nephropathy and progressive renal fibrosis in the Crim1KST264/KST264 mice
School, Centre or Institute Institute for Molecular Bioscience
Institution The University of Queensland
Publication date 2013
Thesis type PhD Thesis
Supervisor Melissa Little
Lorine Wilkinson
Total pages 235
Total colour pages 119
Total black and white pages 116
Language eng
Subjects 0604 Genetics
Formatted abstract
Crim1 is a transmembrane protein which regulates the bioavailability of growth factors such as Vegfa, Tgfβ and Bmps. We have previously shown that the Crim1KST264/KST264 hypomorphic mice developed multiple renal defects characterised by glomerular cysts and loss of endothelial integrity, progressing to peritubular and pericystic fibrosis. In the developing glomerular podocytes, a loss of Crim1 led to dysregulation of Vegfa to the glomerular endothelium, thereby causing a dilation of the glomerular capillaries. Despite the known growth factor regulatory role of Crim1, it is not fully understood how a loss of Crim1 results in the onset of obstructive nephropathy and progression of renal fibrosis in the Crim1KST264/KST264 mice. This PhD project aimed to investigate the mechanisms underlying the urinary obstruction and renal fibrosis in the Crim1KST264/KST264 mice.
Analysis of the Crim1KST264/KST264 hypomorphic mice in this thesis showed that the obstructive phenotype and the renal fibrosis was not directly due to a dysregulated growth factor signalling pathway caused by a loss of Crim1 activity. Rather, these defects were secondary pathological consequences from a papillary hypoplasia which resulted in an early non-productive urinary filtrate clearance from the kidney. This urinary accumulation in turn leads to hydronephrosis in the Crim1KST264/KST264 mice, eventually causing the onset of progressive renal fibrosis which is in part contributed by an Endothelial to Mesenchymal Transition (EndoMT). We also demonstrated that Crim1 is expressed in the papillary interstitium and loops of Henle in a temporal-spatial pattern that coincided with the process of papillary development during the postnatal period.
To further define the Crim1KST264/KST264 papillary hypoplasia phenotype, we first investigated the process of normal papillary growth, followed by analysis of the Crim1KST264/KST264 mice to deduce how a Crim1 growth factor regulatory role is implicated in this process. Our results showed that normal postnatal papillary growth is achieved mainly through convergent-extension of the papillary collecting ducts, in addition to vascular development and canonical Wnt signalling. Convergent-extension results in formation of thin elongated collecting duct during papillaryextension. The papillary hypoplasia in the Crim1KST264/KST264 mice was not due to defective convergent-extension. Instead, reduced canonical Wnt activity, abnormal vascular network and hypoxia were identified. Whether these renal defects are directly caused by a dysregulated growth factor or secondary to placenta insufficiency causing hypoxia remains to be fully elucidated. In conclusion, our analyses of the Crim1KST264/KST264 mice highlight the pathological outcomes of papillary hypoplasia, linking for the first time that inappropriate papillary extension with subsequent hydronephrosis results in progressive fibrosis which is in part derived via EndoMT. This pathological progression should now be considered in assessing chronic kidney disease in patients.
Keyword Crim1
Kidney Diseases
Renal Fibrosis
Periglomerular fibrosis
Endothelial to mesenchymal transition
Glomerular cyst
Endothelial cells
Monocytes
Functional obstruction
Renal papilla
Convergent Extension
Wnt Signaling
Hypoxia
Pericytes
Interstitium
Vasa recta

 
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Created: Tue, 26 Nov 2013, 17:08:06 EST by Mr Yu Leng Phua on behalf of Scholarly Communication and Digitisation Service