Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the ...kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy‐related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells. Deletion of LKB1 or PKD1 in mouse renal tubules elevates CCL2 expression in a cell‐autonomous manner and results in peritubular accumulation of CCR2+ mononuclear phagocytes, promoting a ciliopathy phenotype. Our findings establish an epithelial organelle, the cilium, as a gatekeeper of tissue immune cell numbers. This represents an unexpected disease mechanism for renal ciliopathies and establishes a new model for how epithelial cells regulate immune cells to affect tissue homeostasis.
Synopsis
The cilium instructs immune cell behaviour and tissue homeostasis via a complex of ciliopathy‐related proteins and the kinase LKB1 that together regulate chemokine signalling. Dysregulation of this system presents an unexpected disease mechanism for ciliopathies.
The primary cilium transmits a signal that activates expression of chemokine CCL2.
This signal is regulated through an intra‐ciliary complex of LKB1, NPHP1, polycystin 1 (PC1), ANKS3 and NEK7.
Loss of LKB1 or PC1 increases CCL2 expression and peritubular macrophage numbers and promotes ciliopathy phenotypes.
The Polycystic Kidney Disase (PKD) phenotype seen upon PKD1 depletion is ameliorated in the absence of cilia or tubular CCL2.
A kidney‐specific inactivation of metabolic sensor LKB1 complex reveals a functional crosstalk between primary cilia signaling and aberrant immune cell activation in vivo.
The authors report that INF2 mutations are present in patients with focal segmental glomerulosclerosis (FSGS) associated with Charcot–Marie–Tooth neuropathy. The findings provide insight into ...mechanisms linking formin proteins to podocyte and Schwann-cell function.
Charcot–Marie–Tooth disease refers to a heterogeneous group of inherited chronic peripheral motor and sensory neuropathies.
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Affected persons typically present with progressive distal-muscle weakness and atrophy, reduced tendon reflexes, and foot and hand deformities. Three Charcot–Marie–Tooth disease subtypes have been distinguished by means of electrophysiological and neuropathological studies — a glial myelinopathy (type 1) characterized by slow motor-nerve conduction velocities and demyelinating neuropathy, an axonal form (type 2) associated with normal or subnormal nerve conduction velocities and axonal degeneration, and an intermediate form with demyelinating and axonal features in which patients from the same family may have either subnormal or reduced . . .
In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding
-galactosidase A lead to accumulation of ...globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are poorly replicating, with little ability to compensate for cell loss.
In this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases.
Podocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion-a strong prognosticator of adverse renal outcomes in Fabry disease-as well as with decreasing GFR.
Given the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.
Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the ...major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.
Renal tubular dysgenesis (RTD) is a severe foetal disorder characterised by the absence or poor development of proximal tubules, early onset and persistent anuria (leading to oligohydramnios and the ...Potter sequence) and ossification defects of the skull. In most cases, early death occurs from pulmonary hypoplasia, anuria and refractory arterial hypotension. RTD may be acquired during foetal development or inherited as an autosomal recessive disease. Inherited RTD is genetically heterogeneous and linked to mutations in the genes encoding the major components of the renin–angiotensin system (RAS): angiotensinogen, renin, angiotensin-converting enzyme or angiotensin II receptor type 1. Mutations result in either the absence of production or lack of efficacy of angiotensin II. Secondary RTD has been observed in various situations, particularly in the donor twin of severe twin-to-twin transfusion syndrome, in foetuses affected with congenital haemochromatosis or in foetuses exposed to RAS blockers. All cases result in renal hypoperfusion. These examples illustrate the importance of a functional RAS in the maintenance of blood pressure and renal blood flow for humans during foetal life. The diagnosis of RTD in an anuric foetus with normal renal sonography results is important for the management of the foetus or neonate. Depending on the genetic or secondary cause of the disease, such findings can lead to genetic counselling or the prevention of recurrence in subsequent pregnancies.
Mutations in NPHS1, which encodes nephrin, are the main causes of congenital nephrotic syndrome (CNS) in Finnish patients, whereas mutations in NPHS2, which encodes podocin, are typically responsible ...for childhood-onset steroid-resistant nephrotic syndrome in European populations. Genotype-phenotype correlations are not well understood in non-Finnish patients. We evaluated the clinical presentation, kidney histology, and disease progression in non-Finnish CNS cases by mutational screening in 107 families (117 cases) by sequencing the entire coding regions of NPHS1, NPHS2, PLCE1, WT1, LAMB2, PDSS2, COQ2, and NEPH1. We found that CNS describes a heterogeneous group of disorders in non-Finnish populations. We identified nephrin and podocin mutations in most families and only rarely found mutations in genes implicated in other hereditary forms of NS. In approximately 20% of cases, we could not identify the underlying genetic cause. Consistent with the major role of nephrin at the slit diaphragm, NPHS1 mutations associated with an earlier onset of disease and worse renal outcomes than NPHS2 mutations. Milder cases resulting from mutant NPHS1 had either two mutations in the cytoplasmic tail or two missense mutations in the extracellular domain, including at least one that preserved structure and function. In addition, we extend the spectrum of known NPHS1 mutations by describing long NPHS1 deletions. In summary, these data demonstrate that CNS is not a distinct clinical entity in non-Finnish populations but rather a clinically and genetically heterogeneous group of disorders.
Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity ...mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.
The Renal Lesions of Alport Syndrome HEIDET, Laurence; GUBLER, Marie-Claire
Journal of the American Society of Nephrology,
06/2009, Letnik:
20, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Alport syndrome is a hereditary, progressive, hematuric nephropathy characterized by glomerular basement membrane abnormalities with frequent hearing defects and ocular anomalies. The disease is ...associated with mutations in genes encoding the alpha3, alpha4, or alpha5 chains of type IV collagen, COL4A3, or COL4A4 in the autosomal forms of the disease, COL4A5 in the more frequent X-linked variety. Ultrastructural changes in the glomerular basement membrane and frequent abnormal expression of type IV collagen chains in renal and skin basement membranes are crucial elements for the diagnosis of Alport syndrome, determination of the mode of inheritance, and genetic counseling. Animal models have provided invaluable tools to study the mechanisms leading to progressive deterioration of the glomerular basement membrane and ultimately to renal failure, and to evaluate benefits of potential targeted therapies.
Progressive renal failure often complicates Fabry disease, the pathogenesis of which is not well understood. To further explore this we applied unbiased stereological quantitative methods to electron ...microscopic changes of Fabry nephropathy and the relationship between parameters of glomerular structure and renal function in 14 young Fabry patients (median age 12 years). Renal biopsies were obtained shortly before enzyme replacement therapy from these patients and from nine normal living kidney donors as controls. Podocyte globotriaosylceramide (GL-3) inclusion volume density increased progressively with age; however, there were no significant relationships between age and endothelial or mesangial inclusion volume densities. Foot process width, greater in male Fabry patients, also progressively increased with age compared with the controls, and correlated directly with proteinuria. In comparison to the biopsies of the controls, endothelial fenestration was reduced in Fabry patients. Thus, our study found relationships between quantitative parameters of glomerular structure in Fabry nephropathy and age, as well as urinary protein excretion. Hence, podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.
This study aimed to determine whether early administration of drugs that block the renin–angiotensin system slows the progression of change in glomerular mesangial fractional volume and retinopathy ...progression of two steps or more, according to the retinopathy severity scale. Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy.
Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy.
Diabetic nephropathy, responsible for more than 45% of cases of end-stage renal disease in the United States,
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may be structurally advanced once albuminuria becomes detectable.
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,
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Blockers of the renin–angiotensin system are more effective than other antihypertensive agents in slowing nephropathy progression in patients who have proteinuria, diabetes mellitus, and a reduced glomerular filtration rate (GFR),
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–
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and such blockers can also decrease proteinuria in patients with diabetes.
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Although the reduction of proteinuria in patients with diabetes has been associated with a reduction in the rate of decline in GFR in small studies,
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this association has not been systematically tested; . . .
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