Identification of Structural and Molecular Signatures Mediating Adaptive Changes in the Mouse Kidney in Response to Pregnancy

López-Tello, Jorge; Jiménez-Martínez, María Ángeles; Salazar‐Petres, Esteban; Patel, Ritik; George, Amy L.; Kay, Richard G.; Sferruzzi‐Perri, Amanda N.

doi:10.3390/ijms23116287

Cited by 4 publications

(2 citation statements)

References 78 publications

(90 reference statements)

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“…In human and mouse gestation, kidneys undergo anatomical and hemodynamic changes, to accommodate for increased blood volume, blood pressure regulation, and fetal care 16, 17 . These include increased glomerular filtration rate (GFR) and larger overall organ volume due to increased vascular and interstitial volume 16 .…”

Section: Resultsmentioning

confidence: 99%

The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging

Korin,

Avraham,

Moncada

et al. 2023

Preprint

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The kidney is a complex organ that governs many physiological parameters. It is roughly divided into three parts, the renal pelvis, medulla, and cortex. Covering the cortex is the renal capsule, a serosal tissue that provides protection and forms a barrier for the kidney. Serosal tissues of many organs have been recently shown to play a vital role in homeostasis and disease. Analyses of the cells that reside in these tissues have identified distinct cell types with unique phenotypes. Surprisingly, despite the importance of serosal tissues, little is known about cells of the renal capsule. Here, we characterized this niche and found that it is mainly comprised of fibroblasts and macrophages, but also includes many other diverse cell types. Characterizing renal capsule-associated macrophages, we found that they consist of a distinct subset (i.e., TLF+ macrophages) that is nearly absent in the kidney parenchyma. Injury, disease, and other changes within the kidney, affected the cell composition and phenotype of the renal capsule, indicating its dynamic and vibrant response to changes within the organ parenchyma. Lastly, we studied age-related changes in the renal capsule and found that aging affected the cell composition and pro-inflammatory phenotype of macrophages, increased CD8 T cells and other lymphocyte counts, and promoted a senescence-associated phenotype in fibroblasts. Taken together, our data illustrate the complexity and heterogeneity of the renal capsule and its underlying changes during aging and disease, improving our understanding of the kidney serosa that may be valuable for novel renal therapies.

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Section: Resultsmentioning

confidence: 99%

The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging

Korin,

Avraham,

Moncada

et al. 2023

Preprint

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“…Throughout pregnancy, maternal beta cells within pancreatic islets proliferate, leading to heightened insulin secretion and resistance in maternal tissues, thereby regulating normal blood glucose levels in both humans and mice [ 5 , 6 ]. Additionally, pregnancy increases renal blood flow and the glomerular filtration rate (GFR) in both human and murine models [ 7 , 8 ]. These maternal adjustments are orchestrated by various hormones, including prolactin, which promotes beta-cell expansion in mice [ 6 ], and progesterone and relaxin, which contribute to increased GFR in humans and rats [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Phenotypes of streptozotocin-induced gestational diabetes mellitus in mice

Takahashi,

Ichii,

Hiraishi

et al. 2024

PLoS ONE

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Gestational diabetes mellitus (GDM) in human patients disrupts glucose metabolism post-pregnancy, affecting fetal development. Although obesity and genetic factors increase GDM risk, a lack of suitable models impedes a comprehensive understanding of its pathology. To address this, we administered streptozotocin (STZ, 75 mg/kg) to C57BL/6N mice for two days before pregnancy, establishing a convenient GDM model. Pregnant mice exposed to STZ (STZ-pregnant) were compared with STZ-injected virgin mice (STZ-virgin), citrate buffer-injected virgin mice (CB-virgin), and pregnant mice injected with citrate buffer (CB-pregnant). STZ-pregnant non-obese mice exhibited elevated blood glucose levels on gestational day 15.5 and impaired glucose tolerance. They also showed fewer normal fetuses compared to CB-pregnant mice. Additionally, STZ-pregnant mice had the highest plasma C-peptide levels, with decreased pancreatic islets or increased alpha cells compared to CB-pregnant mice. Kidneys isolated from STZ-pregnant mice did not display histological alterations or changes in gene expression for the principal glucose transporters (GLUT2 and SGLT2) and renal injury-associated markers. Notably, STZ-pregnant mice displayed decreased gene expression of insulin-receiving molecules (ISNR and IGFR1), indicating heightened insulin resistance. Liver histology in STZ-pregnant mice remained unchanged except for a pregnancy-related increase in lipid droplets within hepatocytes. Furthermore, the duodenum of STZ-pregnant mice exhibited increased gene expression of ligand-degradable IGFR2 and decreased expression of GLUT5 and GLUT12 (fructose and glucose transporters, respectively) compared to STZ-virgin mice. Thus, STZ-pregnant mice displayed GDM-like symptoms, including fetal abnormalities, while organs adapted to impaired glucose metabolism by altering glucose transport and insulin reception without histopathological changes. STZ-pregnant mice offer a novel model for studying mild onset non-obese GDM and species-specific differences in GDM features between humans and animals.

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Characterization of placental endocrine function and fetal brain development in a mouse model of small for gestational age

López-Tello

Sferruzzi‐Perri

2023

Front. Endocrinol.

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Conditions such as small for gestational age (SGA), which is defined as birthweight less than 10th percentile for gestational age can predispose to neurodevelopmental abnormalities compared to babies with normal birthweight. Fetal growth and birthweight depend on placental function, as this organ transports substrates to the developing fetus and it acts as a source of endocrine factors, including steroids and prolactins that are required for fetal development and pregnancy maintenance. To advance our knowledge on the aetiology of fetal growth disorders, the vast majority of the research has been focused on studying the transport function of the placenta, leaving practically unexplored the contribution of placental hormones in the regulation of fetal growth. Here, using mice and natural variability in fetal growth within the litter, we compared fetuses that fell on or below the 10th percentile (classified as SGA) with those that had adequate weight for their gestational age (AGA). In particular, we compared placental endocrine metabolism and hormone production, as well as fetal brain weight and expression of developmental, growth and metabolic genes between SGA and AGA fetuses. We found that compared to AGA fetuses, SGA fetuses had lower placental efficiency and reduced capacity for placental production of hormones (e.g. steroidogenic gene Cyp17a1, prolactin Prl3a1, and pregnancy-specific glycoproteins Psg21). Brain weight was reduced in SGA fetuses, although this was proportional to the reduction in overall fetal size. The expression of glucose transporter 3 (Slc2a3) was reduced despite the abundance of AKT, FOXO and ERK proteins were similar. Developmental (Sv2b and Gabrg1) and microglia genes (Ier3), as well as the pregnancy-specific glycoprotein receptor (Cd9) were lower in the brain of SGA versus AGA fetuses. In this mouse model of SGA, our results therefore demonstrate that placental endocrine dysfunction is associated with changes in fetal growth and fetal brain development.

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Identification of Structural and Molecular Signatures Mediating Adaptive Changes in the Mouse Kidney in Response to Pregnancy

Cited by 4 publications

References 78 publications

The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging

The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging

Phenotypes of streptozotocin-induced gestational diabetes mellitus in mice

Characterization of placental endocrine function and fetal brain development in a mouse model of small for gestational age

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