Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth

Mayumi Tomita,Shuichiro Endo,Nariaki Asada,Aris N Economides,Jordan Kreidberg,Elizabeth Robertson,Takeshi Kimura,Jin Nakamura,Misako Asada,Akiko Oguchi,Toru Kita,Motoko Yanagita,Atsuko Y Higashi,Nick Ashton

doi:10.1371/journal.pone.0073554

Abstract

The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarified. Germline knockout of bone morphogenetic protein 7 (Bmp7) results in massive apoptosis of the kidney progenitor cells and defects in early stages of nephrogenesis. This phenotype has precluded analysis of Bmp7 function in the later stage of nephrogenesis. In this study, utilization of conditional null allele of Bmp7 in combination with systemic inducible Cre deleter mice enabled us to analyze Bmp7 function at desired time points during kidney development, and to discover the novel function of Bmp7 to inhibit the precocious differentiation of the progenitor cells to nephron. Systemic knockout of Bmp7 in vivo after the initiation of kidney development results in the precocious differentiation of the kidney progenitor cells to nephron, in addition to the prominent apoptosis of progenitor cells. We also confirmed that in vitro knockout of Bmp7 in kidney explant culture results in the accelerated differentiation of progenitor population. Finally we utilized colony-forming assays and demonstrated that Bmp7 inhibits epithelialization and differentiation of the kidney progenitor cells. These results indicate that the function of Bmp7 to inhibit the precocious differentiation of the progenitor cells together with its anti-apoptotic effect on progenitor cells coordinately maintains renal progenitor pool in undifferentiated status, and determines the nephron number at birth.

Highlights

Over the last decade, the impacts of prenatal conditions on health and disease in later life have been subjects of intense research [1]
We knocked down bone morphogenetic protein 7 (Bmp7) expression through the administration of tamoxifen to pregnant mothers bearing both types of embryos
We demonstrate that Bmp7 inhibits the accelerated differentiation of kidney progenitor cells by utilizing three models, systemic inducible knockout mice, kidney explants and colonyforming assay

Summary

Introduction

The impacts of prenatal conditions on health and disease in later life have been subjects of intense research [1]. Low birth weight is associated with hypertension and a higher risk of diabetes, cardiovascular diseases, and chronic kidney disease [2]. Animal studies and human epidemiological data support the hypothesis that low birth weight is associated with a congenital deficit in nephron number, which results in compensatory glomerular hypertrophy and an increased susceptibility to renal disease progression [3,4,5]. Cap mesenchyme condenses around a tip of the ureteric bud, undergoes epithelialization to form renal vesicles, and differentiates to form most parts of the nephron: podocytes, proximal tubules, Henle’s loops, and distal tubules. Molecular analysis and genetic studies have identified the presence of renal progenitor cells in the cap mesenchyme surrounding the tips of the branching ureteric buds [4,7,8,9,10]

Methods

Results

Conclusion