scholarly journals Extracellular matrix, integrins, and focal adhesion signaling in polycystic kidney disease

2020 ◽  
Vol 72 ◽  
pp. 109646 ◽  
Author(s):  
Yan Zhang ◽  
Gail Reif ◽  
Darren P. Wallace
Keyword(s):  
Extracellular Matrix ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Focal Adhesion ◽  
Polycystic Kidney

scholarly journals Abnormalities in focal adhesion complex formation, regulation, and function in human autosomal recessive polycystic kidney disease epithelial cells

2010 ◽  
Vol 298 (4) ◽  
pp. C831-C846 ◽  
Author(s):  
Sharon Israeli ◽  
Kurt Amsler ◽  
Nadezhda Zheleznova ◽  
Patricia D. Wilson
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Complex Formation ◽  
Polycystic Kidney Disease ◽  
Focal Adhesion ◽  
Autosomal Recessive ◽  
Polycystic Kidney ◽  
Focal Adhesion Complex ◽  
Collecting Tubules ◽  
Adhesion Complex

Integrin-associated focal adhesion complex formation and turnover plays an essential role in directing interactions between epithelial cells and the extracellular matrix during organogenesis, leading to appropriate cell spreading, cell-matrix adhesion, and migration. Autosomal recessive polycystic kidney disease (ARPKD) is associated with loss of function of PKHD1-encoded protein fibrocystin-1 and is characterized by cystic dilation of renal collecting tubules (CT) in utero and loss of renal function in patients if they survive the perinatal period. Normal polycystin-1 (PC-1)/focal adhesion complex function is required for control of CT diameter during renal development, and abnormalities in these complexes have been demonstrated in human PC-1 mutant cystic cells. To determine whether loss of fibrocystin-1 was associated with focal adhesion abnormalities, ARPKD cells or normal age-matched human fetal (HF)CT cells in which fibrocystin-1 had been decreased by 85% by small interfering RNA inhibition were compared with normal HFCT. Accelerated attachment and spreading on collagen matrix and decreased motility of fibrocystin-1-deficient cells were associated with longer paxillin-containing focal adhesions, more complex actin-cytoskeletal rearrangements, and increased levels of total β1-integrin, c-Src, and paxillin. Immunoblot analysis of adhesive cells using site-specific phospho-antibodies demonstrated ARPKD-associated loss of activation of focal adhesion kinase (FAK) by phosphorylation at its autophosphorylation site (Y397); accelerated FAK inhibition by phosphorylation at Y407, S843, and S910; as well as increased activation of c-Src at pY418. Paxillin coimmunoprecipitation analyses suggested that fibrocystin-1 was a component of the normal focal adhesion complex and that actin and fibrocystin-1 were lost from ARPKD complexes.

A possible role for metalloproteinases in renal cyst development

2001 ◽  
Vol 280 (3) ◽  
pp. F540-F550 ◽  
Author(s):  
Nicholas Obermüller ◽  
Natividad Morente ◽  
Bettina Kränzlin ◽  
Norbert Gretz ◽  
Ralph Witzgall
Keyword(s):  
Extracellular Matrix ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Transforming Growth Factor ◽  
Benign Tumors ◽  
Polycystic Kidney ◽  
Essential Matrix ◽  
Metalloproteinase Inhibitor ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Lining

The expansion of cysts in polycystic kidneys bears several similarities to the invasion of the extracellular matrix by benign tumors. We therefore hypothesized that cyst-lining epithelial cells produce extracellular matrix-degrading metalloproteinases and that the inhibition of these enzymes may represent a potential target for therapeutic intervention. Using in situ hybridization, we first analyzed the expression of membrane-type metalloproteinase 1 (MMP-14), an essential matrix metalloproteinase, of its inhibitor TIMP-2, and of the cytokine transforming growth factor (TGF)-β2 in the ( cy/ +) rat model of autosomal-dominant polycystic kidney disease. Upregulated MMP-14 mRNA was predominantly located in cyst-lining epithelia and distal tubules, whereas TIMP-2 mRNA was confined almost exclusively to fibroblasts. TGF-β2, a cytokine known to regulate the expression of matrix metalloproteinases and their inhibitors, was also expressed by cyst wall epithelia. We then treated ( cy/ +) rats with the metalloproteinase inhibitor batimastat for a period of 8 wk. The treatment with the metalloproteinase inhibitor batimastat resulted in a significant reduction of cyst number and kidney weight. Our study suggests that metalloproteinase inhibitors represent a new therapeutic tool against polycystic kidney disease, which should be applicable independently of the background of the disease.

Coexpression of Extracellular Matrix Glycoproteins Undulin and Tenascin in Human Autosomal Dominant Polycystic Kidney Disease

Nephron ◽  
1993 ◽  
Vol 65 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Reinhard Klingel ◽  
Giuliano Ramadori ◽  
Detlef Schuppan ◽  
Thomas Knittel ◽  
Karl-Hermann Meyer zum ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Increased epithelial cell proliferation and abnormal extracellular matrix in rat polycystic kidney disease.

1998 ◽  
Vol 9 (6) ◽  
pp. 937-945 ◽  
Author(s):  
K Ramasubbu ◽  
N Gretz ◽  
S Bachmann
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cyst Formation ◽  
Proliferation Index ◽  
Cystic Degeneration ◽  
Proximal Tubule Cell ◽  
Polycystic Kidney ◽  
Old Rats

Proliferation of renal tubular epithelial cells is considered a major factor leading to cyst formation in human polycystic kidney disease (PKD). The Han:SPRD rat model for inherited PKD permits a close scrutiny, especially for early stages of the disease, and shows numerous similarities to human autosomal dominant PKD (ADPKD). In this study, the exact in vivo proliferation rate in Han:SPRD rat kidneys was evaluated in a cell type-specific manner, using immunohistochemistry with antibody to proliferating cell nuclear antigen (PCNA). The proliferation index (PI; percentage of PCNA-positive cell nuclei) was determined in normal and cystically altered tissue, and a relationship between proliferative activity and alterations in extracellular matrix expression was established using in situ hybridization for collagen I and IV mRNA. Heterozygously affected rats (cy/+) showed strong increases of PI values in cystically altered nephron portions that were mostly derived from proximal tubule. Cell proliferation obviously preceded cyst formation, because early in the progression of the disease, the normal-appearing tubules from PKD kidneys had markedly increased PI values compared with healthy controls (14.1-fold in 3-mo-old rats and 11.9-fold in 12-mo-old rats; P < 0.05), whereas later stages revealed a more generalized cystic degeneration of the nephron, with increases in PI between 14- and 82-fold, depending on the respective category of cystic epithelia. In cysts with a distal phenotype, changes were less pronounced. No significant differences were encountered between the two age groups. Proliferation was also present in interstitial cells, whereas glomeruli were unchanged. Increases in epithelial and interstitial proliferation coincided with an overexpression of matrix compounds. For comparison, changes in homozygously affected rats (cy/cy) showed up to several hundred-fold elevated PI values. These results indicate that in the Han:SPRD model for ADPKD, cystic malformation of the nephron is preceded by and coincides with enhanced epithelial and interstitial cell proliferation. Altered cell-matrix interactions seem to be directly involved in the disruption of epithelial differentiation.

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