R. Ariel Gomez

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  • Phone: 924-2525

Primary Appointment

Professor, Pediatrics- Nephrology

Research Disciplines

Bioinformatics and Genomics, Cardiovascular Biology, Cell and Developmental Biology, Epigenetics, Experimental Pathology, Physiology

Research Interests

Ontogeny of renin-angiotensis system, differentiation of the JG cell.

Research Description

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.

Personal Statement

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.

Selected Publications

Starke C, Betz H, Hickmann L, Lachmann P, Neubauer B, Kopp JB, Sequeira-Lopez ML, Gomez RA, Hohenstein B, Todorov VT, Hugo CP, Renin Lineage Cells Repopulate the Glomerular Mesangium after Injury., 2014; Journal of the American Society of Nephrology : JASN. () . PMID: 24904091

Belyea BC, Xu F, Pentz ES, Medrano S, Li M, Hu Y, Turner S, Legallo R, Jones CA, Tario JD, Liang P, Gross KW, Sequeira-Lopez ML, Gomez RA, Identification of renin progenitors in the mouse bone marrow that give rise to B-cell leukaemia., 2014; Nature communications. 5() 3273. PMID: 24549417 | PMCID: PMC3929784

Gomez RA, Sequeira-Lopez ML, Two oldies join forces to guard homeostasis., 2013; American journal of physiology. Renal physiology. 305(11) F1546. PMID: 24049151

Pentz ES, Cordaillat M, Carretero OA, Tucker AE, Sequeira Lopez ML, Gomez RA, Histone acetyl transferases CBP and p300 are necessary for maintenance of renin cell identity and transformation of smooth muscle cells to the renin phenotype., 2012; American journal of physiology. Heart and circulatory physiology. 302(12) H2545-52. PMID: 22523253 | PMCID: PMC3378259

Brunskill EW, Sequeira-Lopez ML, Pentz ES, Lin E, Yu J, Aronow BJ, Potter SS, Gomez RA, Genes that confer the identity of the renin cell., 2011; Journal of the American Society of Nephrology : JASN. 22(12) 2213-25. PMID: 22034642 | PMCID: PMC3279933

Kurt B, Kurtz L, Sequeira-Lopez ML, Gomez RA, Willecke K, Wagner C, Kurtz A, Reciprocal expression of connexin 40 and 45 during phenotypical changes in renin-secreting cells., 2011; American journal of physiology. Renal physiology. 300(3) F743-8. PMID: 21209011 | PMCID: PMC3064136

Castellanos Rivera RM, Monteagudo MC, Pentz ES, Glenn ST, Gross KW, Carretero O, Sequeira-Lopez ML, Gomez RA, Transcriptional regulator RBP-J regulates the number and plasticity of renin cells., 2011; Physiological genomics. 43(17) 1021-8. PMID: 21750232 | PMCID: PMC3180736

Medrano S, Monteagudo MC, Sequeira-Lopez ML, Pentz ES, Gomez RA, Two microRNAs, miR-330 and miR-125b-5p, mark the juxtaglomerular cell and balance its smooth muscle phenotype., 2011; American journal of physiology. Renal physiology. 302(1) F29-37. PMID: 21993888 | PMCID: PMC3251334

Sequeira Lopez ML, Gomez RA, Development of the renal arterioles., 2011; Journal of the American Society of Nephrology : JASN. 22(12) 2156-65. PMID: 22052047 | PMCID: PMC3250202

Wagner C, Jobs A, Schweda F, Kurtz L, Kurt B, Lopez ML, Gomez RA, van Veen TA, de Wit C, Kurtz A, Selective deletion of Connexin 40 in renin-producing cells impairs renal baroreceptor function and is associated with arterial hypertension., 2010; Kidney international. 78(8) 762-8. PMID: 20686449 | PMCID: PMC3033195

Sequeira-Lopez ML, Weatherford ET, Borges GR, Monteagudo MC, Pentz ES, Harfe BD, Carretero O, Sigmund CD, Gomez RA, The microRNA-processing enzyme dicer maintains juxtaglomerular cells., 2010; Journal of the American Society of Nephrology : JASN. 21(3) 460-7. PMID: 20056748 | PMCID: PMC2831866

Desch M, Schreiber A, Schweda F, Madsen K, Friis UG, Weatherford ET, Sigmund CD, Sequeira Lopez ML, Gomez RA, Todorov VT, Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells., 2010; Hypertension. 55(3) 660-6. PMID: 20065157 | PMCID: PMC2907524

Chen L, Kim SM, Eisner C, Oppermann M, Huang Y, Mizel D, Li L, Chen M, Sequeira Lopez ML, Weinstein LS, Gomez RA, Schnermann J, Briggs JP, Stimulation of renin secretion by angiotensin II blockade is Gsalpha-dependent., 2010; Journal of the American Society of Nephrology : JASN. 21(6) 986-92. PMID: 20395378 | PMCID: PMC2900955

Sequeira Lopez ML, Gomez RA, Novel mechanisms for the control of renin synthesis and release., 2010; Current hypertension reports. 12(1) 26-32. PMID: 20425155 | PMCID: PMC2861778

Lopez ML, Gomez RA, The renin phenotype: roles and regulation in the kidney., 2010; Current opinion in nephrology and hypertension. 19(4) 366-71. PMID: 20502328 | PMCID: PMC3079389

Chen L, Faulhaber-Walter R, Wen Y, Huang Y, Mizel D, Chen M, Sequeira Lopez ML, Weinstein LS, Gomez RA, Briggs JP, Schnermann J, Renal failure in mice with Gsalpha deletion in juxtaglomerular cells., 2010; American journal of nephrology. 32(1) 83-94. PMID: 20551626 | PMCID: PMC2914394

Xu D, Borges GR, Davis DR, Agassandian K, Sequeira Lopez ML, Gomez RA, Cassell MD, Grobe JL, Sigmund CD, Neuron- or glial-specific ablation of secreted renin does not affect renal renin, baseline arterial pressure, or metabolism., 2010; Physiological genomics. 43(6) 286-94. PMID: 21189370 | PMCID: PMC3068515