CBP and p300 are essential for renin cell identity and morphological integrity of the kidney

Abstract

The mechanisms that govern the identity of renin cells are not well understood. We and others have identified cAMP as an important pathway in the regulation of renin synthesis and release. Recently, experiments in cells from the renin lineage led us to propose that acquisition and maintenance of renin cell identity are mediated by cAMP and histone acetylation at the cAMP responsive element (CRE) of the renin gene. Ultimately, the transcriptional effects of cAMP depend on binding of the appropriate transcription factors to CRE. It has been suggested that access of transcription factors to this region of the promoter is facilitated by the coactivators CREB-binding protein (CBP) and p300, which possess histone acetyltransferase activity and may be, in turn, responsible for the remodeling of chromatin underlying expression of the renin gene. We hypothesized that CBP and p300 are therefore required for expression of the renin gene and maintenance of the renin cell. Because mice homozygous for the deletion of CBP or p300 die before kidney organogenesis begins, no data on kidney or juxtaglomerular cell development in these mice are available. Therefore, to define the role of these histone acetyltransferases in renin cell identity in vivo, we used a conditional deletion approach, in which floxed CBP and p300 mice were crossed with mice expressing cre recombinase in renin cells. Results show that the histone acetyltransferases CBP and p300 are necessary for maintenance of renin cell identity and structural integrity of the kidney.

Development of the Renal Arterioles

“…Recently, in vitro and in vivo studies demonstrate the crucial role of the cAMP pathway on the acquisition and maintenance of the renin cell identity. 51,52 Activation of the cAMP pathway was proven to be of importance not only for the well known stimulation of renin release but also for vascular development early in fetal life. Conditional deletion of G␣ s in cells from the renin lineage such as arteriolar SMCs and mesangial cells results in almost complete absence of renin-expressing cells in the fetal kidney accompanied by blunted development of the preglomerular arterial tree.…”

Transcriptional regulator RBP-J regulates the number and plasticity of renin cells

“…Serial sections (5 m) were deparaffinized in xylenes and graded alcohols. Sections were processed for immunohistochemistry for renin and ␣-smooth muscle actin and stained with hematoxylin or with Masson's trichrome (to assess collagen deposition) as previously described (8,32). To visualize renin granules, 2 m kidney sections were deparaffinized through xylenes and graded alcohols followed by a wash with PBS for 5 min.…”

“…RNA extraction and cDNA generation by reverse transcription and quantitative real-time PCR using SYBR Green (Invitrogen, Eugene, OR) were performed as previously described (8). Renin mRNA expression was normalized to GAPDH expression.…”

Chronic kidney disease in children and the role of epigenetics: Future therapeutic trajectories

“…Using a cultured renin linage cell system, studies observed that its gene expression memory is maintained in the cultured cells and may be re-enacted by cAMP and chromatin remodeling (histone H4 acetylation) (44). Other investigators also noted that CREB-binding protein and p300 (which possess histone acetyltransferase activity) are vital for renin cell distinctiveness, as well as the integrity of the renal architecture (45).…”