Research Interest

Identity of the renin cell and homeostasis

One of the most elusive questions in renal vascular biology is the origin and fate of renin-expressing juxtaglomerular (JG) cells.

Renin is a crucial hormone that controls blood pressure and fluid-electrolyte and kidney homeostasis. In adult mammals, renin is synthesized and released to the circulation by the JG cells, a small group of granulated cells located in the wall of the afferent arteriole at the entrance to the glomerulus. We have shown that during embryonic development, renin-expressing cells are broadly distributed along large intrarenal arteries, inside the glomeruli and in the renal interstitium. As maturation continues the number of renin cells is progressively restricted to a few cells in the JG area of the adult kidney.

The developmental pattern of renin cell distribution is relevant to understand the phenomenon of recruitment, a survival mechanism whereby a threat to homeostasis such as dehydration or hypotension elicits an increase in the number of renin-expressing cells along preglomerular arteries, inside the glomeruli, and in the kidney interstitium resembling the fetal pattern. The increase in the number of renin-expressing cells (with the resulting increase in circulating renin) does not involve migration or replication of cells, but suggested a reacquision of the renin cell phenotype. To test this hypothesis and determine the lineage and fate of renin cells, we generated mice harboring cre recombinase under the control of the ren1d locus. The experiments showed that renin cells are not terminally differentiated as previously thought but they are instead progenitors for arteriolar smooth-muscle, mesangial, tubular and interstitial cells and it is these adult cells that de-differentiate and re-express renin when additional hormone is required to reestablish homeostasis. Thus, the ability of adult cells to synthesize this crucial hormone does not occur randomly in any cell type but depends instead on the cell's lineage. Recently, we developed a variety of in vitro and in vivo systems that allowed us to identify cAMP as a major determinant of renin cell identity, an effect that is mediated by chromatin remodeling at the cAMP responsive element in the renin gene. In addition to epigenetic events, we identified a set of microRNAs that bind the 3'UTR of renin mRNA and are expressed in kidney vascular and renin cells in specific patterns within the kidney arterioles. We are currently testing the hypothesis that these microRNAs may be responsible for the progressive restriction of renin expression along the kidney vasculature during kidney development.

Publications

Sequeira Lopez MLS, Pentz ES, Nomasa T, Smithies O, Gomez, RA. Renin-expressing cells are precursors for multiple cell types capable of switching to the rennin phenotype when homeostasis is threatened. (Developmental) Cell 6(5): 71928, 2004.

Pentz, E. S., M. A. Moyano, B. A. Thornhill, M. L. Sequeira Lopez, and R. A. Gomez.. Ablation of renin-expressing juxtaglomerular cells results in a distinct kidney phenotype. Am. J. Physiol Regul. Integr. Comp Physiol 286:R474-R483, 2004.

Takahashi, N., M. L. Lopez, J. E. Cowhig, Jr., M. A. Taylor, T. Hatada, E. Riggs, G. Lee, R. A. Gomez, H. S. Kim, and O. Smithies. Ren1c homozygous null mice are hypotensive and polyuric, but heterozygotes are indistinguishable from wild-type. J. Am. Soc. Nephrol. 16:125-132, 2005.

Lee G, Makhanova N, Caron K, lopez ML, Gomez RA , Smithies O, Kim HS. Homeostatic responses in the adrenal cortex to the absence of aldosterone in mice. Endocrinology 146:2650-6, 2005.

Makhanova N, Lee G, Takahashi N, Sequeira Lopez ML, Gomez RA, Kim HS, Smithies O: Kidney function in mice lacking aldosterone. Am J Physiol Renal Physiol. 290:F61-9, 2006.

Chen L, Kim SM, Opperman M, Faulhaber-Walter R, Huang Y, MIzel D, Chen M, Sequeira Lopez ML, Weistein LS, Gomez RA, Briggs JP, Schnermann J: Regulation of renin in mice with cre recombinase-mediated deletion of G protein Gsa in juxtaglomerular cells. Am J Physiol Renal Physiol 292:F27-F37, 2007.

Pentz ES, Lopez ML, Cordaillat M, Gomez RA: Identity of the renin cell is mediated by cAMP and chromatin remodeling: an invitro model for studying cell recruitment and plasticity. Am J Physiol Heart Circ Physiol 294:H699-H707, 2008.

For more information email rg@virginia.edu.