Expression profiles of congenital renal dysplasia reveal new insights into renal development and disease

Abstract

Congenital renal dysplasia (RD) is a major cause of renal failure in the pediatric population. Although molecular and genetic aspects of RD have been studied in animal models, limited studies have been done in human RD primarily due to lack of available material. To identify novel genes that are associated with RD and normal kidney development, we performed microarray analysis on total RNA extracted from age-matched fetal kidneys of normal and RD patients. In midgestational RD kidneys, we found 180 upregulated and 104 downregulated transcripts compared with normal kidneys. Among the increased transcripts in the dysplastic kidneys were matrix-degrading enzymes (MMP7, MMP19, TIMP1), inflammation- and immunity-related genes, and growth factors. Expression of genes known to be essential for normal kidney development, such as WT1, BMP7, renin, angiotensin receptor 2 (AGTR2), SAL-like 1 (SALL1) and glypican 3 (GPC3), were decreased in dysplastic kidneys. Expression of selected gene products (BMP7, renin, and MMP7) was further confirmed in parallel sections and in several normal and human dysplastic kidneys, supporting the role of these genes as putative RD biomarkers. These results are among the first to reveal disrupted expression profiles during gestation in human RD patients.

β-Catenin Causes Renal Dysplasia via Upregulation of Tgfβ2 and Dkk1

“…TGF␤2 is expressed in the basement membrane surrounding ureteric cells during kidney development and decreases ureteric branching and nephrogenesis when applied to embryonic kidney explant cultures, 40 and is upregulated in human fetal dysplastic tissue. 41 Furthermore, Tgf␤2 heterozygous mice are characterized by increased ureteric branch length and nephron number, consistent with a physiologic inhibitory effect of Tgf␤2 in vivo. 31 Combined, these results support a role for TGF␤2 inhibiting ureteric branching in ␤-cat…”

Regulation and function of Spalt proteins during animal development

“…Some patients present deletions of the whole SALL1 gene and, in fact, they show a rather mild TBS phenotype, reinforcing the idea that the haploinsuffi-ciency is not enough to cause the severe classical TBS symptoms . Confirming the role of Sall1 in kidney formation, SALL1 expression is reduced in patients with congenital dysplastic kidneys, a major cause of renal failure in infants (Jain et al, 2007), as well as in congenital obstructive nephropathy, a common disease affecting foetuses and young children (Table 3; Liapis, 2003). Mice homozygous for Sall1 show kidney agenesis and die in the perinatal period.…”

Does therapeutic angiogenesis overcome CKD?

“…In particular, mutations in SALL1 result in Townes-Brocks syndrome, a rare autosomal-dominant malformation syndrome characterized by dysplastic ears, pre-axial polydactyly and/or triphalangeal thumbs, imperforate anus, renal malformations and cardiac anomalies. 17 Confirming the role of Sall1 in kidney formation, SALL1 expression is reduced in patients with congenital dysplastic kidneys, a major cause of renal failure in infants, 11 as well as in congenital obstructive nephropathy, a common disease affecting the fetus and young children. 12 In contrast, murine Sall1 was seen to function as a transcriptional repressor of the artificial promoter containing tandem GAL4-binding sites, when linked to the heterologous GAL4 DNA-binding domain, and also Sall1 was associated with HDAC and several components of the chromatin-remodeling complex.…”

“…Human SALL1 has been described as a transcriptional repressor in a number of experimental settings, most of them involving the regulation of heterologous promoters fused to reporter genes. 10 SALL1 gene expression is related to some human congenital diseases 11,12,15,[17][18][19] (Figure 2). In particular, mutations in SALL1 result in Townes-Brocks syndrome, a rare autosomal-dominant malformation syndrome characterized by dysplastic ears, pre-axial polydactyly and/or triphalangeal thumbs, imperforate anus, renal malformations and cardiac anomalies.…”

“…10 It is unclear whether Sall1 affects vascular development, but Sall1 may induce renal organogenesis through angiogenic properties. SALL1 expression is reduced in patients with 7 congenital dysplastic kidneys, 11 as well as in congenital obstructive nephropathy 12 (Figure 2), so therapeutic angiogenesis by SALL1 gene transfer may rescue the kidney in patients with CKD.…”