Laura Kidd

Prorenin receptor is critical for nephron progenitors

Deficient nephrogenesis is the major factor contributing to renal hypoplasia defined as abnormally small kidneys. Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H(+)-ATPase. Global loss of PRR is lethal in mice and PRR mutations are associated with a high blood pressure, left ventricular hypertrophy and X-linked mental retardation in humans. To circumvent lethality of the ubiquitous PRR mutation in mice and to determine the potential role of the PRR in nephrogenesis, we generated a mouse model with a conditional deletion of the PRR in Six2(+) nephron progenitors and their epithelial derivatives (Six2(PRR-/-)). Targeted ablation of PRR in Six2(+) nephron progenitors caused a marked decrease in the number of developing nephrons, small cystic kidneys and podocyte foot process effacement at birth, and early postnatal death. Reduced congenital nephron endowment resulted from premature depletion of nephron progenitor cell population due to impaired progenitor cell proliferation and loss of normal molecular inductive response to canonical Wnt/β-catenin signaling within the metanephric mesenchyme. At 2 months of age, heterozygous Six2(PRR+/-) mice exhibited focal glomerulosclerosis, decreased kidney function and massive proteinuria. Collectively, these findings demonstrate a cell-autonomous requirement for the PRR within nephron progenitors for progenitor maintenance, progression of nephrogenesis, normal kidney development and function.

Differences in placental telomere length suggest a link between racial disparities in birth outcomes and cellular aging

Background: Health disparities begin early in life and persist across the life course. Despite current efforts, black women exhibit greater risk for pregnancy complications and negative perinatal outcomes compared with white women. The placenta, which is a complex multi‐tissue organ, serves as the primary transducer of bidirectional information between the mother and fetus. Altered placental function is linked to multiple racially disparate pregnancy complications; however, little is known about racial differences in molecular factors within the placenta. Several pregnancy complications, which include preeclampsia and fetal growth restriction, exhibit racial disparities and are associated with shorter placental telomere length, which is an indicator of cellular stress and aging. Cellular senescence and telomere dynamics are linked to the molecular mechanisms that are associated with the onset of labor and parturition. Further, racial differences in telomere length are found in a range of different peripheral tissues. Together these factors suggest that exploration of racial differences in telomere length of the placenta may provide novel mechanistic insight into racial disparities in birth outcomes. Objective: This study examined whether telomere length measured in 4 distinct fetally derived tissues were significantly different between black and white women. The study had 2 hypotheses: (1) that telomere length that is measured in different placental tissue types would be correlated and (2) that across all sampled tissues telomere length would differ by race. Study Design: In a prospective study, placental tissue samples were collected from the amnion, chorion, villus, and umbilical cord from black and white singleton pregnancies (N=46). Telomere length was determined with the use of monochrome multiplex quantitative real‐time polymerase chain reaction in each placental tissue. Demographic and pregnancy‐related data were also collected. Descriptive statistics characterized the sample overall and among black and white women separately. The overall impact of race was assessed by multilevel mixed‐effects linear regression models that included empirically relevant covariates. Results: Telomere length was correlated significantly across all placental tissues. Pairwise analyses of placental tissue telomere length revealed significantly longer telomere length in the amnion compared with the chorion (t=–2.06; P=.043). Overall telomere length measured in placenta samples from black mothers were significantly shorter than those from white mothers (&bgr;=–0.09; P=.04). Controlling for relevant maternal and infant characteristics strengthened the significance of the observed racial differences (&bgr;=–0.12; P=.02). Within tissue analyses revealed that the greatest difference by race was found in chorionic telomere length (t=–2.81; P=.007). Conclusion: These findings provide the first evidence of racial differences in placental telomere length. Telomere length was significantly shorter in placental samples from black mothers compared with white mothers. Given previous studies that have reported that telomere length, cellular senescence, and telomere dynamics are molecular factors that contribute to the rupture of the amniotic sac, onset of labor, and parturition, our findings of shorter telomere length in placentas from black mothers suggest that accelerated cellular aging across placental tissues may be relevant to the increased risk of preterm delivery in black pregnancies. Our results suggest that racial differences in cellular aging in the placenta contribute to the earliest roots of health disparities.

Conditional ablation of the prorenin receptor in nephron progenitor cells results in developmental programming of hypertension

Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells (NPCs) of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump V‐ATPase. Previously, we demonstrated that conditional ablation of the PRR in Six2+ NPCs in mice (Six2PRR−/−) causes early neonatal death. Here, we identified genes that are regulated by PRR in Six2+ NPCs FACS‐isolated from Six2PRR−/− and control kidneys on embryonic day E15.5 using whole‐genome expression analysis. Seven genes with expression in CM cells previously shown to direct kidney development, including Notch1, β‐catenin, Lef1, Lhx1, Jag1, and p53, were downregulated. The functional groups within the downregulated gene set included genes involved in embryonic and cellular development, renal regeneration, cellular assembly and organization, cell morphology, death and survival. Double‐transgenic Six2PRR−/−/BatGal+ mice, a reporter strain for β‐catenin transcriptional activity, showed decreased β‐catenin activity in the UB in vivo. Reduced PRR gene dosage in heterozygous Six2PRR+/− mice was associated with decreased glomerular number, segmental thickening of the glomerular basement membrane with focal podocyte foot process effacement, development of hypertension and increased soluble PRR (sPRR) levels in the urine at 2 months of age. Together, these data demonstrate that NPC PRR performs essential functions during nephrogenesis via control of hierarchy of genes that regulate critical cellular processes. Both reduced nephron endowment and augmented urine sPRR likely contribute to programming of hypertension in Six2PRR+/− mice.

Membranoproliferative Glomerulonephritis in Pregnancy

Background: Membranoproliferative glomerulonephritis (MPGN) is an uncommon form of glomerulonephritis and it can be particularly difficult to predict outcomes and manage women with this disorder during pregnancy. Materials and Methods: The management of 3 successful pregnancies in women with MPGN from 1 center and previously described cases from the world literature are reviewed. This includes a number of large studies of pregnancy in women with underlying glomerular disease as well as small case series and individual reports. Courses of these pregnancies, maternal and fetal outcomes, and management, when described, were included in this review. Results: Some successful outcomes used antiplatelet therapy and plasmapheresis, but high‐dose intravenous, followed by oral, corticosteroid therapy was used most frequently in patients with successful outcomes. Conclusions: The data provided is meant as a guide for clinicians who provide care for women with MPGN who are considering pregnancy or women who present with this disorder while pregnant.

Membranoproliferative Glomerulonephritis in Pregnancy: 3 Successful Outcomes at 1 Institution

Background: Membranoproliferative glomerulonephritis (MPGN) is an uncommon form of glomerulonephritis and it can be particularly difficult to predict outcomes and manage women with this disorder during pregnancy. Materials and Methods: The management of 3 successful pregnancies in women with MPGN from 1 center and previously described cases from the world literature are reviewed. This includes a number of large studies of pregnancy in women with underlying glomerular disease as well as small case series and individual reports. Courses of these pregnancies, maternal and fetal outcomes, and management, when described, were included in this review. Results: Some successful outcomes used antiplatelet therapy and plasmapheresis, but high‐dose intravenous, followed by oral, corticosteroid therapy was used most frequently in patients with successful outcomes. Conclusions: The data provided is meant as a guide for clinicians who provide care for women with MPGN who are considering pregnancy or women who present with this disorder while pregnant.

Clinical InvestigationMembranoproliferative Glomerulonephritis in Pregnancy

Background: Membranoproliferative glomerulonephritis (MPGN) is an uncommon form of glomerulonephritis and it can be particularly difficult to predict outcomes and manage women with this disorder during pregnancy. Materials and Methods: The management of 3 successful pregnancies in women with MPGN from 1 center and previously described cases from the world literature are reviewed. This includes a number of large studies of pregnancy in women with underlying glomerular disease as well as small case series and individual reports. Courses of these pregnancies, maternal and fetal outcomes, and management, when described, were included in this review. Results: Some successful outcomes used antiplatelet therapy and plasmapheresis, but high‐dose intravenous, followed by oral, corticosteroid therapy was used most frequently in patients with successful outcomes. Conclusions: The data provided is meant as a guide for clinicians who provide care for women with MPGN who are considering pregnancy or women who present with this disorder while pregnant.