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bioRxiv · 10.1101/2022.07.01.497442

The extracellular matrix protein fibronectin modulates metanephric kidney development

Skoczynski, K.·Kraus, A.·Buettner-Herold, M.·Amann, K.·Schiffer, M.·Hermann, K.·Herrnberger, L.·Tamm, E. R.·Buchholz, B.
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Abstract

Complex interactions of the branching ureteric bud and surrounding mesenchymal cells during metanephric kidney development determine the final number of nephrons. Alterations that result in impaired nephron endowment predispose to arterial hypertension and chronic kidney disease. In the kidney, extracellular matrix (ECM) proteins are usually regarded as acellular scaffolds or as the common histological end-point of chronic kidney diseases. Only little is known about their physiological role in kidney development. The ECM protein fibronectin is expressed at early time points of kidney growth. Therefore, we were interested in the characterization of its expression and role in kidney development. In mouse, fibronectin was expressed during all stages of kidney development with significant changes over time. At embryonic day (E) 12.0 and E13.5 fibronectin lined the ureteric bud epithelium, which was less pronounced at E16.5 and then switched to a glomerular expression in the postnatal and adult kidneys. Similar results were obtained in human kidneys. Deletion of fibronectin at E13.5 in cultured metanephric mouse kidneys resulted in reduced kidney sizes, impaired branching morphogenesis and decreased glomerulogenesis. In line with these findings, fibronectin deletion led to reduced cell proliferation of the branching epithelial cells. Fibronectin colocalized with alpha8 integrin and fibronectin loss caused a reduction in alpha8 integrin-dependent formation of glial cell line-derived factor and expression of Wnt11, both of which are essentially involved in promoting ureteric bud branching. In conclusion, the ECM protein fibronectin acts as a regulator of metanephric kidney development and is a determinant of nephron number.

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Skoczynski, K., Kraus, A., Buettner-Herold, M., Amann, K., Schiffer, M., Hermann, K., Herrnberger, L., Tamm, E. R., Buchholz, B.. 2022-07-02. The extracellular matrix protein fibronectin modulates metanephric kidney development. https://doi.org/10.1101/2022.07.01.497442

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