Abstract
The development of the mammalian kidney is a highly complex process dependent upon the interplay of various cell types, secreted morphogens, and the extra-cellular matrix (ECM). Although integrins are the most important receptors for ECM proteins and are ubiquitously expressed during kidney development, mice lacking expression of integrin α3 (Itga3) do not demonstrate a reduced number of nephrons, but mostly a disorganized GBM (glomerular basement membrane) leading to proteinuria. Thus, ITGA3 is considered mostly a passive GBM stabilizer and not an active player in nephrogenesis. Recently, mutations in the human ITGA3 were shown to cause congenital nephrotic syndrome, epidermolysis bullosa and interstitial lung disease, otherwise termed NEP syndrome (Nephrotic syndrome, Epidermolysis bullosa and Pulmonary disease). Herein, we performed histological and molecular analysis on the kidneys of a single patient from the initial cohort harboring an ITGA3 mutation, to illuminate the role of ITGA3 in human renal development. We show the patient to harbor a unique phenotype at birth, including severe unilateral renal hypodysplasia. Interrogation of global gene expression in the hypodysplastic kidney versus three controls (fetal, child and adult kidneys) revealed perturbed expression in several renal developmental pathways implicated in hypodysplasia, including the Wnt, BMP (bone morphogenetic protein) and TGF (transforming growth factor) pathways. Moreover, the affected kidney showed upregulation of early embryonic genes (e.g. OCT4 and PAX8) concomitant with downregulated kidney differentiation markers, implying a defect in proper renal differentiation. In conclusion, we show for the first time that ITGA3 is not merely a passive anchor for renal ECM proteins, as predicted by mouse models. Instead, our results may suggest it plays a central role in the interplay of cells, morphogens and ECM, required for proper nephrogenesis, thus adding ITGA3 to the list of CAKUT (congenital anomalies of the kidney and urinary tract)-causing genes.
Highlights
The formation of the metanephric kidney occurs via the concerted actions of several important factors
Because renal hypodysplasia is not included in the phenotypic spectrum of NEP syndrome [11], further investigation was performed on tissue samples obtained during post mortem analysis
Having observed this renal developmental phenotype we screened nine candidate kidney developmental genes known to be associated with renal hypodysplasia
Summary
The formation of the metanephric kidney occurs via the concerted actions of several important factors. These findings are consistent with the high levels of Itga expression in immature podocytes, endothelial, and mesangial cells during kidney development [6]. Itga3-null mice show decreased branching of the medullary collecting ducts, the number of nephrons is normal [7], suggesting that aside from its role in GBM formation and stabilization, ITGA3 has a rather limited role in nephrogenesis and is not considered a CAKUT (congenital anomalies of the kidney and urinary tract)-causing gene This assertion was confirmed when mice lacking Itga in UB cells demonstrated a surprisingly subtle phenotype, showing decreased papillary outgrowth [9]. As previously mentioned, kidney development is highly dependent upon reciprocal interactions between the UB and MM, requiring complex cell–ECM interactions [10]
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