Research Interests
Transcriptional specification of terminal differentiation.
Terminal differentiation is a crucial step in development whereby cell cycle exit is coordinated with expression of physiological functions. In the kidney, failure of terminal differentiation is a leading cause of diseases such as dysplasia, cystogenesis, and cancer. However, there is little known regarding the steps of terminal differentiation and the specification of individual renal epithelial cell types. The laboratory is examining the role of the tumor suppressor protein, p53, in terminal differentiation of the renal epithelium. p53 is a transcription factor that is highly enriched in differentiating renal epithelial cells. Ongoing studies are evaluating the interactions of p53 with the promoter elements of terminal differentiation genes in the kidney. Studies using cells expressing mutant forms of p53 and mice either lacking or overexpressing kidney-specific p53 are being produced to determine the role of p53 in renal development. We are beginning to understand the molecular pathways that couple renal epithelial cell growth with functional differentiation.
Epigenetic control of organogenesis and differentiation.
In recent years, the nucleosome has emerged as an active participant in the transcriptional regulation of gene expression. Histone acetylation favors the access of transcription factors to the promoter regulatory elements. In contrast, histone deacetylation causes gene silencing. We have evidence that histone deacetylases (HDACs) are essential for the development of the embryonic kidney. Gene expression analysis indicates that HDACs are required for the expression of genes necessary for ureteric bud branching morphogenesis. Moreover, HDACs are required to silence terminal differentiation genes – inhibition of HDAC activity induces premature expression of these differentiation markers and impairs kidney growth and development. We are currently investigating how alterations in histone acetylation alter the expression of renal development genes, and we hope to identify a common “histone code” in these genes. We also hope to generate conditional kidney-specific deletion of the “renal” HDACs in order to elucidate their individual roles in renal organogenesis and differentiation.
Gene-environment interactions in renal development
Renal dysplasia is a common cause of chronic kidney failure in infants and children. To better understand the pathways leading to renal dysgenesis, we have developed a mouse model of human renal dysplasia. The bradykinin B2 receptor is a G-protein-coupled receptor that plays key roles in regulation of cell growth, inflammation and blood pressure. In normal mice, B2 receptors are expressed in the renal collecting ducts. Targeted disruption of the bradykinin B2 receptor gene in mice has no major consequences on development. However, gestational salt loading results in abnormal collecting duct formation (cysts) in the offspring. The renal dysplasia is observed during fetal life and the affected null pups die soon after birth presumably from renal failure. The laboratory is now in the process of identifying the pathways involved in the renal dysgenesis utilizing differential gene expression methodology. The in vivo relevance of the identified genes will be tested by either overexpression or deletion from the B2 receptor knockout background.
Selected Publications:
Yosypiv IV, Boh MK, Spera M, and El-Dahr SS. Downregulation of Spry-1, an Inhibitor of GDNF/Ret, as a Mechanism for Angiotensin II-Induced Ureteric Bud Branching. Kidney International. In press
El-Dahr SS, Aboudehen K, Dipp S. Bradykinin B2 receptor null mice harboring a Ser23-to-Ala substitution in the p53 gene are protected from renal dysgenesis. Am. J. Physiol. (Renal). In press
El-Dahr SS, Aboudehen K, Saifudeen Z. Transcriptional control of terminal nephron differentiation. Am. J. Physiol. (Renal Physiol). 294:F1273-8, 2008.
Madeddu P, Costanza E and El-Dahr SS. The kallikrein-kinin system in hypertension and vascular remodeling. Nature Clin. Practice Neph. 3: 208-221, 2007.
Shen B, Harrison-Bernard LM, Vanderpool V, Saifudeen Z, and El-Dahr SS. The bradykinin B2 receptor gene is a target for angiotensin II type 1 receptor signaling. J. Am. Soc. Nephrol. 18: 1140-1149, 2007.
Van Bodegom D, Saifudeen Z, Dipp S, Magenheimer BS, Calvet JP, and El-Dahr SS. The polycystic kidney disease-1 gene is a target for p53-mediated transcriptional repression. J. Biol. Chem. 281:31234-31244, 2006.
Fan H, Stefkova J, and El-Dahr SS. Susceptibility to Metanephric Apoptosis in Bradykinin B2 Receptor Null Mice via the p53-Bax Pathway. Am. J. Physiol. (Renal Physiol.) 291: 670-682, 2006.
Yosypiv IV, Schroeder M, and El-Dahr SS. Angiotensin II type 1-EGFR cross talk regulates ureteric bud branching morphogenesis. J. Am. Soc. Nephrol. 17: 1005-1014, 2006.
Saifudeen Z, Diavolitsis V, Dipp S, Fan, H, and El-Dahr SS. Spatiotemporal switch from DNp73 to TAp73 isoforms during nephrogenesis: impact on differentiation gene expression. J. Biol. Chem. 280: 23094 – 23102, 2005.
Saifudeen Z, Dipp S, Fan H, and El-Dahr SS. Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4 and CBP: Implications for terminal nephron differentiation. Am. J. Physiol. (Renal Physiol). 288: F899-F909, 2005. [Editorial Focus in the same issue, F897].
Fan H, Harrell J, Dipp S, Saifudeen Z, and El-Dahr SS. A novel pathological role of p53 in kidney development revealed by gene-environment interactions. Am. J. Physiol (Renal Physiol.) 288: F98-F107, 2005.
Marks J., Saifudeen Z., Dipp S., and El-Dahr S. S. Two functionally divergent p53-responsive elements in the bradykinin B2 receptor promoter. J. Biol. Chem. 278: 34158-34166, 2003.
Saifudeen Z., Marks J., Du H., and El-Dahr S. S. Spatial repression of PCNA by p53 during kidney development. Am. J. Physiol. 283: F727-F733, 2002.
Saifudeen, Z., Dipp, S. and El-Dahr S. S. A role for p53 in terminal epithelial cell differentiation. J. Clin. Invest 109: 1021-1030, 2002.
Saifudeen, Z., Du, H., Dipp, S. and El-Dahr, S. S.. The bradykinin type 2 receptor is a target for p53-mediated transcriptional activation. J. Biol. Chem. 275:15557-155562, 2000.
El-Dahr, S. S., Harrison-Bernard, L. M., Dipp, S., Yosipiv, I. V. and Meleg-Smith, S. Bradykinin B2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development. Physiological Genomics 3:121-131, 2000.
Contact info: seldahr@tulane.edu