Partitioning-Defective 1a/b Depletion Impairs Glomerular and Proximal Tubule Development

Abstract

The kidney is a highly polarized epithelial organ that develops from undifferentiated mesenchyme, although the mechanisms that regulate the development of renal epithelial polarity are incompletely understood. Partitioning-defective 1 (Par1) proteins have been implicated in cell polarity and epithelial morphogenesis; however, the role of these proteins in the developing kidney has not been established. Therefore, we studied the contribution of Par1a/b to renal epithelial development. We examined the renal phenotype of newborn compound mutant mice carrying only one allele of Par1a or Par1b. Loss of three out of four Par1a/b alleles resulted in severe renal hypoplasia, associated with impaired ureteric bud branching. Compared with kidneys of newborn control littermates, kidneys of newborn mutant mice exhibited dilated proximal tubules and immature glomeruli, and the renal proximal tubular epithelia lacked proper localization of adhesion complexes. Furthermore, Par1a/b mutants expressed low levels of renal Notch ligand Jag1, activated Notch2, and Notch effecter Hes1. Together, these data demonstrate that Par1a/b has a key role in glomerular and proximal tubule development, likely via modulation of Notch signaling.

Proximal Tubular Development Is Impaired with Downregulation of MAPK/ERK Signaling, HIF-1α, and Catalase by Hyperoxia Exposure in Neonatal Rats

“…Proximal tubule dilation is a common pathological abnormality in urinary tract obstruction, acute kidney injury, and renal dysplasia [24, 44, 45]; of these, acute kidney injury is considered a hyperoxia-induced lesion [13]. We found that neonatal hyperoxia contributed to abnormal proximal tubule dilation in adult rats.…”

“…Proximal tubular cells differentiate from the distal domain of S-shaped bodies during nephrogenesis [24]. HIF-1 α and catalase expression in S-shaped bodies was investigated in order to identify the initial response of proximal tubular cells to neonatal hyperoxia.…”

“…Briefly, a grid of dots, 13 μ m apart, was superimposed on images. No dilation was defined as no dots within lumens, and tubular dilation was defined as more than one dot within each tubular lumen [24]. Tubular cell number was counted automatically using ImageJ 1.51 as per the protocol described by Parlee et al [25].…”

Notch Signaling in Kidney Development, Maintenance, and Disease

“…In spite of having a large set of subjects, a clear genetic correlation with kidney disease was not made. Another study examining the genome-wide cytosine methylation pattern of tubular epithelial cells micro-dissected from human kidneys of control and DKD subjects identified changes in the methylation levels predictive of altered gene expression levels of important renal transcription factors [114]. Exact mechanism for upregulation of Notch pathway is unknown at this time.…”

The Evolving Complexity of the Podocyte Cytoskeleton

“…[51][52][53] The importance of podocyte polarity signaling is also supported by the high level of redundancy of the involved molecules. [54][55][56] In addition, loss-offunction mutations in the gene encoding the polarity protein CRUMBS2 have been shown to result in steroid-resistant nephrotic syndrome. 57…”