Primary cilia disappear in rat podocytes during glomerular development

Parietal podocytes are fully differentiated podocytes lining Bowman's capsule where normally only parietal epithelial cells (PECs) are found. Parietal podocytes form throughout life and are regularly observed in human biopsies, particularly in atubular glomeruli of diseased kidneys; however, the origin of parietal podocytes is unresolved. To assess the capacity of PECs to transdifferentiate into parietal podocytes, we developed and characterized a novel method for creating atubular glomeruli by electrocoagulation of the renal cortex in mice. Electrocoagulation produced multiple atubular glomeruli containing PECs as well as parietal podocytes that projected from the vascular pole and lined Bowman's capsule. Notably, induction of cell death was evident in some PECs. In contrast, Bowman's capsules of control animals and normal glomeruli of electrocoagulated kidneys rarely contained podocytes. PECs and podocytes were traced by inducible and irreversible genetic tagging using triple transgenic mice (PEC-or Pod-rtTA/LC1/R26R). Examination of serial cryosections indicated that visceral podocytes migrated onto Bowman's capsule via the vascular stalk; direct transdifferentiation from PECs to podocytes was not observed. Similar results were obtained in a unilateral ureter obstruction model and in human diseased kidney biopsies, in which overlap of PEC-or podocyte-specific antibody staining indicative of gradual differentiation did not occur. These results suggest that induction of atubular glomeruli leads to ablation of PECs and subsequent migration of visceral podocytes onto Bowman's capsule, rather than transdifferentiation from PECs to parietal podocytes.

Section: Discussionmentioning

confidence: 99%

Origin of Parietal Podocytes in Atubular Glomeruli Mapped by Lineage Tracing

Schulte

Berger

Boor

et al. 2014

“…Ichimura et al demonstrated in the rat kidney that most fetal podocytes present a primary cilium at the S-shaped body and capillary loop stages that gradually disappears during glomerular maturation. 10 In human fetal kidney sections, we showed that podocytes, labeled by nephrin, also display cilia at the S-shaped and capillary loop stages ( Figure 2C, upper and middle panels, Supplemental Figure 3C). Moreover, we detected IFT139 staining in the cytoplasm of fetal podocytes, notably at the base of the primary cilium ( Figure 2C, upper and middle panels).…”

mentioning

confidence: 88%

A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS

Cong

Bizet

Boyer

et al. 2014

Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.

“…However, whereas in immature rat glomeruli, podocytes express cilia, these tend to disappear during development. 74 Hence, our identification of a missense mutation (p.P209L) in the TTC21B gene encoding the intraflagellar transport (IFT) 139 protein in seven families with hereditary focal-segmental glomerulosclerosis, discovered during late adolescence or early adulthood, raised the question of a role of IFT139 (and potentially other IFT proteins) beyond the primary cilium. 75 Mutations in TTC21B had previously been reported in patients with nephronophthisis, 76 but careful reanalysis of the clinical and histologic features of all patients bearing the p.P209L mutation clearly showed that they present with both glomerular and tubulointerstitial involvement.…”

Section: Corinne Antignacmentioning

confidence: 99%

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

Antignac

Calvet

Germino

et al. 2015

Polycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases. Jared J. Grantham, M.D., has done more than any other individual to promote PKD research around the world. However, despite decades of investigation there is still no approved therapy for PKD in the United States. In May 2014, the University of Kansas Medical Center hosted a symposium in Kansas City honoring the occasion of Dr. Grantham's retirement and invited all the awardees of the Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease to participate in a forward-thinking and interactive forum focused on future directions and innovations in PKD research. This article summarizes the contributions of the 12 Kaplan awardees and their vision for the future of PKD research.