Developmental Programming of CKD

Background: Chronic kidney disease (CKD) is growing in prevalence throughout the world. However, the developmental origins of CKD mechanisms remain largely unknown. Gestational effect is believed to be mediated by gene expression reprogramming, including epigenetic changes. Methods: To determine the significance of epigenetic regulation by histone deacetylases (HDACs) in the programming of CKD, we established an intrauterine growth restriction (IUGR) mouse model by feeding the pregnant mice 6% protein diet (low protein diet, LPD) throughout gestation, while the control group was fed with isocaloric 20% protein diet (normal protein diet, NPD). Results: Gross and histological examination of IUGR mice at P0 showed smaller kidney size, smaller nephrogenic zone, fewer nephrons, increased interstitial collagen, cellular infiltration, and tubular atrophy, compared to the control group. Immunostaining results also demonstrated a diminished nephrogenic zone with a smaller Six2+ progenitor pool and nascent nephron deficit in P0 IUGR kidney (p<0.001, n=4). The glomeruli number of P21 pups was found to be about 20% reduction in LPD pups compared to NPD group. Additionally, our results indicate concurrent overactive Hdac1/2 and reduced expression of Bmp7 (both at mRNA and protein levels) in the developing kidneys of IUGR mice. To investigate transcriptional regulation of Bmp7 by HDAC1/2 in mammalian nephron progenitor cells, we performed Chromatin Immunoprecipitation Sequencing for Hdac1 and Hdac2 in isolated E16.5 NPCs and demonstrated the binding of Hdac1/2 to Bmp7 enhancer in vivo. Consistently, loss of Hdac1/2 leads to an obvious augmentation of Bmp7 expression in developing kidney of conditional knock-out mice. Sirius red and Masson’s Trichrome Staining indicated an increased fibrosis extracellularin the kidneys of IUGR mice at age of 15 months. We also detected a significantly higher level of α-SMA and fibronectin in IUGR Kidneys. Conclusion: Together, our findings demonstrate that IUGR predisposes to CKD by reprograming renal development via aberrant activation of Hdac1/2, which in turn represses Bmp7 expression.A mechanistic determination of how Hdac1/2-Bmp7 mediates CKD will provide a novel link between overactive HDAC1/2 to the developmental origin of CKD and effective clinical approaches to prevention and treatment of kidney disease and fibrosis. Funding: Private Foundation Support