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Project description:Periconceptual maternal iron deficiency (FeD) is a worldwide problem resulting in prematurity and low birth weights. Yet, it is not known whether FeD affects all developing tissues, or rather targets specific lineages. To address these questions, we investigated the targeting of the kidney by FeD. We found that FeD reduced both serum transferrin-iron and non-transferrin-bound-iron (NTBI), and these deficiencies targeted the renal proximal nephron rather than renal collecting ducts or stroma. In contrast, proximal tubular deletions of TfR1 (TfD) caused only modest defects in kidney development implying compensation by NTBI in the embryo. Yet, after the first two postnatal weeks, proximal TfD resulted in striking segmentally specific hypoplasia, as well as well as pervasive cystic transformation with Bardet-Biedel or Nephronothesis protein deficiencies. Treatment with NTBI as well as systemic activators of HIF which induce iron trafficking bypassed TfD and rescued the cystic disease and suppressed kidney damage. In sum, iron depletion resulted in new forms of chronic kidney disease. Its phenotype resulted from the alternative use of two different forms of iron, NTBI and Tf-iron at different stages and in different cells of the developing kidney.
2025-09-08 | GSE100252 | GEO
Project description:Periconceptual maternal iron deficiency (FeD) is a worldwide problem resulting in prematurity and low birth weights. Yet, it is not known whether FeD affects all developing tissues, or rather targets specific lineages. To address these questions, we investigated the targeting of the kidney by FeD. We found that FeD reduced both serum transferrin-iron and non-transferrin-bound-iron (NTBI), and these deficiencies targeted the renal proximal nephron rather than renal collecting ducts or stroma. In contrast, proximal tubular deletions of TfR1 (TfD) caused only modest defects in kidney development implying compensation by NTBI in the embryo. Yet, after the first two postnatal weeks, proximal TfD resulted in striking segmentally specific hypoplasia, as well as well as pervasive cystic transformation with Bardet-Biedel or Nephronothesis protein deficiencies. Treatment with NTBI as well as systemic activators of HIF which induce iron trafficking bypassed TfD and rescued the cystic disease and suppressed kidney damage. In sum, iron depletion resulted in new forms of chronic kidney disease. Its phenotype resulted from the alternative use of two different forms of iron, NTBI and Tf-iron at different stages and in different cells of the developing kidney.
2025-09-08 | GSE100253 | GEO
Project description:Periconceptual maternal iron deficiency (FeD) is a worldwide problem resulting in prematurity and low birth weights. Yet, it is not known whether FeD affects all developing tissues, or rather targets specific lineages. To address these questions, we investigated the targeting of the kidney by FeD. We found that FeD reduced both serum transferrin-iron and non-transferrin-bound-iron (NTBI), and these deficiencies targeted the renal proximal nephron rather than renal collecting ducts or stroma. In contrast, proximal tubular deletions of TfR1 (TfD) caused only modest defects in kidney development implying compensation by NTBI in the embryo. Yet, after the first two postnatal weeks, proximal TfD resulted in striking segmentally specific hypoplasia, as well as well as pervasive cystic transformation with Bardet-Biedel or Nephronothesis protein deficiencies. Treatment with NTBI as well as systemic activators of HIF which induce iron trafficking bypassed TfD and rescued the cystic disease and suppressed kidney damage. In sum, iron depletion resulted in new forms of chronic kidney disease. Its phenotype resulted from the alternative use of two different forms of iron, NTBI and Tf-iron at different stages and in different cells of the developing kidney.
2025-09-08 | GSE100251 | GEO
Project description:A Switch in Iron Transport Mechanisms Defines Novel Forms of Congenital Chronic Kidney Disease
| PRJNA391158 | ENA
Project description:The ballistic regime of vibrational energy transport in oligomeric molecular chains occurs with a constant, often high, transport speed and high efficiency. Such a transport regime can be initiated by exciting a chain end group with a mid-infrared (IR) photon. To better understand the wavepacket formation process, two chemically identical end groups, azido groups with normal, 14N3-, and isotopically substituted, 15N3-, nitrogen atoms, were tested for wavepacket initiation in compounds with alkyl chains of n = 5, 10, and 15 methylene units terminated with a carboxylic acid (-a) group, denoted as 14N3Cn-a and 15N3Cn-a. The transport was initiated by exciting the azido moiety stretching mode, the νN≡N tag, at 2100 cm-1 (14N3Cn-a) or 2031 cm-1 (15N3Cn-a). Opposite to the expectation, the ballistic transport speed was found to decrease upon 14N3 → 15N3 isotope editing. Three mechanisms of the transport initiation of a vibrational wavepacket are described and analyzed. The first mechanism involves the direct formation of a wavepacket via excitation with IR photons of several strong Fermi resonances of the tag mode with the νN═N + νN-C combination state while each of the combination state components is mixed with delocalized chain states. The second mechanism relies on the vibrational relaxation of an end-group-localized tag into a mostly localized end-group state that is strongly coupled to multiple delocalized states of a chain band. Harmonic mixing of νN═N of the azido group with CH2 wagging states of the chain permits a wavepacket formation within a portion of the wagging band, suggesting a fast transport speed. The third mechanism involves the vibrational relaxation of an end-group-localized mode into chain states. Two such pathways were found for the νN≡N initiation: The νN═N mode relaxes efficiently into the twisting band states and low-frequency acoustic modes, and the νN-C mode relaxes into the rocking band states and low-frequency acoustic modes. The contributions of the three initiation mechanisms in the ballistic energy transport initiated by νN≡N tag are quantitatively evaluated and related to the experiment. We conclude that the third mechanism dominates the transport in alkane chains of 5-15 methylene units initiated with the νN≡N tag and the wavepacket generated predominantly at the CH2 twisting band. The isotope effect of the transport speed is attributed to a larger contribution of the faster wavepackets for 14N3Cn-a or to the different breadth of the wavepacket within the twisting band. The study offers a systematic description of different transport initiation mechanisms and discusses the requirements and features of each mechanism. Such analysis will be useful for designing novel materials for energy management.
| S-EPMC8287563 | biostudies-literature
Project description:Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci and combined autozygome analysis and whole-exome sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction. Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level. This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change. Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation.
| S-EPMC4240208 | biostudies-literature
Project description:ObjectivesTo quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation.MethodsHigh-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly.ResultsEnlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation.ConclusionsIncreased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.
| S-EPMC4922485 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy. Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.
| S-EPMC2302790 | biostudies-literature
Project description:Systemic iron metabolism is disrupted in chronic kidney disease (CKD). However, little is known about local kidney iron homeostasis and its role in kidney fibrosis. Kidney-specific effects of iron therapy in CKD also remain elusive. Here, we elucidate the role of macrophage iron status in kidney fibrosis and demonstrate that it is a potential therapeutic target. In CKD, kidney macrophages exhibited depletion of labile iron pool (LIP) and induction of transferrin receptor 1, indicating intracellular iron deficiency. Low LIP in kidney macrophages was associated with their defective antioxidant response and proinflammatory polarization. Repletion of LIP in kidney macrophages through knockout of ferritin heavy chain (Fth1) reduced oxidative stress and mitigated fibrosis. Similar to Fth1 knockout, iron dextran therapy, through replenishing macrophage LIP, reduced oxidative stress, decreased the production of proinflammatory cytokines, and alleviated kidney fibrosis. Interestingly, iron markedly decreased TGF-β expression and suppressed TGF-β-driven fibrotic response of macrophages. Iron dextran therapy and FtH suppression had an additive protective effect against fibrosis. Adoptive transfer of iron-loaded macrophages alleviated kidney fibrosis, validating the protective effect of iron-replete macrophages in CKD. Thus, targeting intracellular iron deficiency of kidney macrophages in CKD can serve as a therapeutic opportunity to mitigate disease progression.
| S-EPMC9870080 | biostudies-literature
Project description:Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). The kidney recycles iron back into the circulation. However, the localization of proteins relevant for physiological tubular iron handling and their potential role in CKD remain unclear. We examined associations between iron deposition, expression of iron handling proteins and tubular injury in kidney biopsies from CKD patients and healthy controls using immunohistochemistry. Iron was deposited in proximal (PT) and distal tubules (DT) in 33% of CKD biopsies, predominantly in pathologies with glomerular dysfunction, but absent in controls. In healthy kidney, PT contained proteins required for iron recycling including putative iron importers ZIP8, ZIP14, DMT1, iron storage proteins L- and H-ferritin and iron exporter ferroportin, while DT only contained ZIP8, ZIP14, and DMT1. In CKD, iron deposition associated with increased intensity of iron importers (ZIP14, ZIP8), storage proteins (L-, H-ferritin), and/or decreased ferroportin abundance. This demonstrates that tubular iron accumulation may result from increased iron uptake and/or inadequate iron export. Iron deposition associated with oxidative injury as indicated by heme oxygenase-1 abundance. In conclusion, iron deposition is relatively common in CKD, and may result from altered molecular iron handling and may contribute to renal injury.
| S-EPMC6008459 | biostudies-literature