Gomez, R. Ariel
Professor, Pediatrics: Nephrology
Bioinformatics and Genomics, Cardiovascular Biology, Cell and Developmental Biology, Epigenetics, Experimental Pathology, Physiology
Ontogeny of renin-angiotensis system, differentiation of the JG cell.
Renin-synthesizing cells are crucial in the regulation of blood pressure and fluid and electrolyte homeostasis. These cells have been considered as terminally differentiated because they synthesize a hormone, are few in numbers, and their restricted juxtaglomerular (JG) localization. However, during embryonic development, and kidney morphogenesis, renin cells are widely distributed and do not become circumscribed to a "classical" JG localization until later in postnatal life. In addition, during early development renin expression precedes the expression of smooth muscle proteins suggesting that renin cells may be precursors for other cell types including but not limited to JG cells. To address this issue, we generated mice that express cre recombinase under the control of the renin locus and crossed them with reporter mice that after cre-mediated recombination express Beta-galactosidase or GFP in renin cells and its descendants even if renin expression subseq uently ceases, therefore marking the cells' lineage. The results indicate that in addition to JG cells, renin cells are precursors for multiple cell types, including renal vascular smooth muscle, mesangial, tubular epithelial, and extrarenal cells such as Leydig and adrenal cells. Physiological manipulations showed that those differentiated cells, retain the memory to synthesize renin when homeostasis is threatened, and re-differentiate when the crisis passes.
In addition to their role as precursors for other cell types, renin cells may have other functions. To test whether renin cells per se are important in kidney development we generated a mouse model in which renin cells are absent. Whereas the kidney phenotype of this mouse is similar in many respects to the phenotypes obtained with deletion of genes of the renin-angiotensin system, a striking difference was the absence of vascular abnormalities such as arteriolar thickening and diminished branching characteristic of those models lacking angiotensin action. In fact, the vessels of mice lacking JG cells were thinner with a diminished number of smooth muscle cells suggesting that the presence of renin cells was linked to the vascular abnormalities observed in animals deficient in angiotensin. Altogether, the experiments suggest that renin cells may not only be physiological sensors but may also be necessary for the maintenance of the morphological and physiological integrity of the kidney.