CKD and chronic hypoxia

Recent studies have emphasized the role of chronic hypoxia in the tubulointerstitium as a final common pathway in end-stage renal disease,1 and showed that hypoxia in the kidney induces pro-fibrotic changes.2 Hence, oxygenation in the kidney is likely to be a critical determinant of its life. In this context, renal protective effects of angiogenic factors, such as vascular endothelial growth factor (VEGF),3 hepatocyte growth factor4 and hypoxia-inducible factor,5 are reported with some problems6, 7, 8 (Figure 1).

Figure 1
figure 1

Therapeutic angiogenesis for kidney disease were reported using VEGF, HGF and HIF. Each factor has a merit and demerit. The function of sall1 is not so clear, but sall1 may promote renal organogenesis. HGF; hepatocyte growth factor, HIF; hypoxia-inducible factor, EMT; epithelial–mesenchymal transformation.

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This issue of Hypertension Research includes a paper by Noboru Fukuda and coworkers that addresses the effect of Sall1 on angiogenesis.9 The Sall1 gene is required for multiple developmental processes, and regulates morphogenesis and organogenesis especially in the kidney. On the other hand, VEGF has a critical role in renal development by promoting endothelial cell differentiation, capillary formation and proliferation of tubular epithelial cells, so the authors investigated the relationship between Sall1 and VEGF. Sall1 gene transfer induces capillary neovascular formation in the rat cornea and mouse embryoid bodies, and increases VEGF-A promoter activity in HEK293T cells. This angiogenesis is inhibited by anti-VEGF neutralizing antibody. Sall1-deficient mice show severe renal dysplasia or complete renal agenesis, but normal vascular development.10 It is unclear whether Sall1 affects vascular development, but Sall1 may induce renal organogenesis through angiogenic properties. SALL1 expression is reduced in patients with7 congenital dysplastic kidneys,11 as well as in congenital obstructive nephropathy12 (Figure 2), so therapeutic angiogenesis by SALL1 gene transfer may rescue the kidney in patients with CKD.

Figure 2
figure 2

SALL1 expression is reduced in patients with Townes–Brocks syndrome, congenital dysplastic kidneys and congenital obstructive nephropathy. On the other hand, SALL1 expression is induced in patients with trophoblast tumors, sex hormone-producing tumors, Wilm’s tumor and testicular carcinoma.

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Sall1 is a member of spalt family

The homeotic spalt gene of Drosophila melanogaster determines the identity of the anterior head and the posterior tail regions during early development.13, 14 At later stages, spalt is involved in the development of the wing disk, trachea and sensory organs.15, 16 Humans and mice have four functional spalt-related genes, SALL1 to SALL4 (Sall1 to Sall4 in mice). The human SALL1 gene encodes transcription factors with a characteristic structure of evenly distributed zinc-finger domains. 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 diseases11, 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.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.20, 21 Therefore, Sall1 could repress gene expression by recruiting the HDAC complex. On the other hand, Nishinakamura et al.22 reported that the native form of Sall1 could function as a transcriptional activator in Wnt signaling, which is essential for many developmental processes, and that its activity correlated with its localization to heterochromatin. An increase in Sall1 proteins may squelch some transcriptional repressor complex, including HDAC, or be associated with chromatin-remodeling factors to alter the chromatin structure near the promoter region of Wnt target genes.

Sall1 and renal stem cell

Moreover, Sall1 is necessary for the activation of some kidney mesenchymal markers, consistent with its role in ureteric bud invasion. Homozygous deletion in mice induces severe defects in the kidney, which indicates that Sall1 has an essential role in kidney development. Murine Sall1 has a role in maintaining cellular pluripotency and proliferation.10 Thus, renal primordial cells in the ureteric bud epithelium and metanephric mesenchyme are able to produce nephrons and collecting ducts when induced from pluripotent embryonic stem cells. Only cells expressing high levels of Sall1 can reconstitute a three-dimensional kidney structure in an organ culture setting, indicating that renal progenitors with multipotent capacity require Sall1.23, 24 In these cells, Sall1 is not required for the generation or differentiation of renal progenitors, but for their proliferation or survival.23

Does SALL1 gene transfer overcome CKD?

Potentially, SALL1 gene transfer may improve hypoxia through VEGF-induced angiogenesis and promote renal organogenesis to counteract CKD. VEGF is an essential molecule for glomerular structure, but recently deleterious effects of VEGF have been demonstrated in diabetic nephropathy.6 Careful monitoring is therefore required in its use in CKD patients with diabetes.