Nephronectin Regulates Mesangial Cell Adhesion and Behavior in Glomeruli.

A critical aspect of kidney function occurs at the glomerulus, the capillary network that filters the blood. The glomerular basement membrane (GBM) is a key component of filtration, yet our understanding of GBM interactions with mesangial cells, specialized pericytes that provide structural stability to glomeruli, is limited. We investigated the role of nephronectin (Npnt), a GBM component and known ligand of α8ß1 integrin. Immunolocalization and in situ hybridization studies in kidneys of adult mice revealed that nephronectin is produced by podocytes and deposited into the GBM. Conditional deletion of Npnt from nephron progenitors caused a pronounced increase in mesangial cell number and mesangial sclerosis. Nephronectin colocalized with α8ß1 integrin to novel, specialized adhesion structures that occurred at sites of mesangial cell protrusion at the base of the capillary loops. Absence of nephronectin disrupted these adhesion structures, leading to mislocalization of α8ß1. Podocyte-specific deletion of Npnt also led to mesangial sclerosis in mice. These results demonstrate a novel role for nephronectin and α8ß1 integrin in a newly described adhesion complex and begin to uncover the molecular interactions between the GBM and mesangial cells, which govern mesangial cell behavior and may have a role in pathologic states.

Maturation of the olfactory sensory neurons by Apaf-1/caspase-9-mediated caspase activity.

Although the apoptotic role of caspases has been largely understood, accumulating evidence in Drosophila suggests that caspases also control other processes than apoptotic cell death. However, how caspases contribute to the development of the mammalian nervous system remains obscure. Here, we provide unique evidence that Apaf-1/caspase-9-mediated caspase signaling regulates the development of olfactory sensory neurons (OSNs), which includes axonal projection, synapse formation, and maturation of these neurons. This caspase signaling leads to a cleavage of Semaphorin 7A, a membrane-anchored semaphorin that is required for the proper axonal projection. Mutant mice deficient for apaf-1 or caspase-9 exhibit misrouted axons, impaired synaptic formation, and defects in the maturation of OSNs without affecting the number of these cells. Our findings suggest that Apaf-1/caspase-9-mediated nonapoptotic caspase signaling is required for the proper neural network formation during olfactory development.

A case of atypical congenital nephrotic syndrome.

We present a female newborn with the nephrotic syndrome of intrauterine onset and a unique set of extrarenal abnormalities, as well as atypical renal lesions. The extrarenal anomalies comprised a soft tissue hemangioma in the frontotemporal region, unilateral microphthalmia (with persistent hyperplastic corpus vitreous and detachment of the retina), and glaucoma in the other eye. Immature glomeruli and/or glomeruli with large cellular crescents were found in renal biopsy specimens in the 3rd week of life. On autopsy, 7 weeks later, diffuse mesangial sclerosis (DMS) was the predominant type of glomerular lesion. In addition, dilations of tubules, forming microcysts, as well as clusters of infiltrating cells in the interstitium, were found both in renal biopsy and autopsy specimens. Although the symptoms observed in our patient did not match any reported in association with the known forms of the congenital nephrotic syndrome (CNS), the most probable diagnosis seemed to be CNS due to DMS of intrauterine onset, with superimposed drug-related tubulointerstitial nephritis.

Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the glomerular basement membrane.

In developing glomeruli, laminin alpha5 replaces laminin alpha1 in the glomerular basement membrane (GBM) at the capillary loop stage, a transition required for glomerulogenesis. To investigate domain-specific functions of laminin alpha5 during glomerulogenesis, we produced transgenic mice that express a chimeric laminin composed of laminin alpha5 domains VI through I fused to the human laminin alpha1 globular (G) domain, designated Mr51. Transgene-derived protein accumulated in many basement membranes, including the developing GBM. When bred onto the Lama5 -/- background, Mr51 supported GBM formation, preventing the breakdown that normally occurs in Lama5 -/- glomeruli. In addition, podocytes exhibited their typical arrangement in a single cell layer epithelium adjacent to the GBM, but convolution of glomerular capillaries did not occur. Instead, capillaries were distended and exhibited a ballooned appearance, a phenotype similar to that observed in the total absence of mesangial cells. However, here the phenotype could be attributed to the lack of mesangial cell adhesion to the GBM, suggesting that the G domain of laminin alpha5 is essential for this adhesion. Analysis of an additional chimeric transgene allowed us to narrow the region of the alpha5 G domain essential for mesangial cell adhesion to alpha5LG3-5. Finally, in vitro studies showed that integrin alpha3beta1 and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin alpha5. Our results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the GBM.

Number of glomeruli is increased in the kidney of transgenic mice expressing the truncated type II activin receptor.

Histological analyses of the kidney were performed in transgenic mice expressing the truncated type II activin receptor. In these mice, signaling through the activin receptor was attenuated. Size and wet weight of the kidneys were identical to those of normal mice. Histologically, the number of glomeruli was approximately 180% of that in normal mice. The sizes and shapes of the glomeruli were variable, but many of them were smaller than those in normal mice. Morphometrically, the total glomerular area was 130% of that of the normal mice. Abnormality of the epithelia in Bowman's capsule was observed and the number of tubular epithelial cells was increased in the transgenic mice. The serum levels of blood urea nitrogen, creatinine, and creatinine clearance were identical to those in normal mice. These results suggest that the action of activin or related ligands is critical for determination of the nephron number.