Histone deacetylases are critical regulators of the renin-angiotensin system during ureteric bud branching morphogenesis.
Mutations in the genes encoding components of the renin-angiotensin system (RAS) in mice or humans cause congenital abnormalities of the kidney and urinary tract. We hypothesized that absence of angiotensin (Ang) II in angiotensinogen (AGT)-deficient mice leads to defects in ureteric bud (UB) branching and that RAS genes are critically dependent on histone deacetylase (HDAC) activity. The number of UB tips was lower in AGT-/- compared with AGT+/+ embryonic (E) day E13.5 metanephroi (24+/-1.5 versus 36+/-3.7, p<0.05). Real-time RT-PCR demonstrated that pharmacological inhibition of HDAC activity with Scriptaid increases AGT, renin, angiotensin-converting enzyme (ACE), and AT1 receptor (AT1R) mRNA levels in E12.5 mouse metanephroi and early mesenchymal (MK3) cells. Furthermore, Scriptaid enhanced Ang II induced decrease in Sprouty (Spry) 1 gene expression in cultured UB cells. Treatment of intact E12.5 mouse metanephroi grown ex vivo with Ang II (10(-5) M, 24 h) increased HDAC-1 and decreased total acetylated histone H3 protein levels. These findings indicate that lack of endogenous Ang II in AGT-deficient mice inhibits UB branching. We conclude that intact RAS is critical in structural integrity of the renal collecting system and that UB morphogenetic program genes, such as AGT, renin, ACE, AT1R, or Spry1, are epigenetically controlled via HDACs.
Song
Renfang
R
Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Van Buren
Thomas
T
Yosypiv
Ihor V
IV
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000808:Angiotensinogen / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006898:Hydroxylamines / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D010750:Phosphoproteins / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D046509:Tissue Culture Techniques; D014513:Ureter / Q000187:drug effects / Q000196:embryology / Q000201:enzymology*
D048868:Adaptor Proteins, Signal Transducing; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006898:Hydroxylamines; D008565:Membrane Proteins; D010750:Phosphoproteins; D011804:Quinolines; D012333:RNA, Messenger; C425468:Spry1 protein, mouse; C410733:scriptaid; D000808:Angiotensinogen; D000804:Angiotensin II; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1