Low birth weight is associated with impaired murine kidney development and function

Abstract

BACKGROUND: Low birth weight (LBW) neonates have impaired kidney development that leaves them susceptible to kidney disease and hypertension during adulthood. The study here identifies events that blunt nephrogenesis and kidney development in the murine LBW neonate. METHODS: We examined survival, kidney development, GFR, gene expression, and cyto-/chemokines in the LBW offspring of malnourished (caloric and protein-restricted) pregnant mice. RESULTS: Malnourished pregnant mothers gave birth to LBW neonates that had 40% reduced body weight and 54% decreased survival. Renal blood perfusion was reduced by 37%, whereas kidney volume and GFR were diminished in the LBW neonate. During gestation, the LBW neonatal kidney had 2.2-fold increased apoptosis, 76% decreased SIX2+ progenitor cells, downregulation of mesenchymal-to-epithelial signaling factors Wnt9b and Fgf8, 64% less renal vesicle formation, and 32% fewer nephrons than controls. At birth, increased plasma levels of IL-1β, IL-6, IL-12(p70), and granulocyte-macrophage colony-stimulating factor in the LBW neonate reduced SIX2+ progenitor cells. CONCLUSION: Increased pro-inflammatory cytokines in the LBW neonate decrease SIX2+ stem cells in the developing kidney. Reduced renal stem cells (along with the decreased mesenchymal-to-epithelial signaling) blunt renal vesicle generation, nephron formation, and kidney development. Subsequently, the mouse LBW neonate has reduced glomeruli volume, renal perfusion, and GFR.

Analysis of structure and gene expression in developing kidneys of male and female rats exposed to low protein diets in utero

“…Although cardiovascular and renal disease may arise via several mechanisms, increasing evidence from human and animal studies implicates low nephron number as being central to the disease process (Douglas‐Denton, McNamara, Hoy, Hughson, & Bertram, 2006; Hoy, Hughson, Singh, Douglas‐Denton, & Bertram, 2006; Low Birth Weight and Nephron Number Working Group, 2017; Luyckx et al, 2013; Wang & Garrett, 2017). The number of nephrons in normal human kidneys is directly correlated with birth weight, with low birth weight a proxy marker of a sub‐optimal intrauterine environment (Barnett et al, 2017; Hughson et al, 2008; Hughson, Farris 3rd, Douglas‐Denton, Hoy, & Bertram, 2003; Lackland & Barker, 2009). Animal studies have shown that a maternal low protein (LP) diet, typically associated with low birth weight, results in offspring with 20–30% fewer nephrons than control kidneys (Boubred et al, 2016; Hoppe, Evans, Moritz, et al, 2007; Hoppe, Evans, Bertram, & Moritz, 2007; Langley & Jackson, 1994; Langley‐Evans, 1997; Langley‐Evans et al, 1999; McMullen & Langley‐Evans, 2005; Sahajpal & Ashton, 2003; Woods, Ingelfinger, Nyengaard, & Rasch, 2001; Woods, Weeks, & Rasch, 2004; Zimanyi et al, 2006).…”

The Role of Cellular Stress in Intrauterine Growth Restriction and Postnatal Dysmetabolism

“…Of note, these changes occurred exclusively in three-month-old offspring after catch-up growth had occurred, suggesting that catch-up growth may be responsible for the observed cardiac deficits. Nephrogenesis and renal function are also impeded in IUGR offspring via reduced nephron endowment, making these offspring further susceptible to hypertension and chronic kidney disease [67]. Studies of maternal malnutrition have identified the protein fetuin-B as having a role in this process, leading to increased generation of ROS in the kidneys of low birth weight offspring [68].…”

Ontogeny and Cross-species Comparison of Pathways Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Neonates (Review): Kidney

“…There is variation in RBF results between different methods in adult mice. Data on the 1st weeks after birth are sparse, but Barnett et al (2017) showed a rapid increase in renal perfusion from PND 0 [70 laser Doppler flowmetry (LDF) arbitrary units] to PND 3 (180 LDF arbitrary units) and PND 7 (280 LDF arbitrary units) in CD-1 mice.…”