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

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.

Development of the Mammalian Kidney

“…Bmp7 is expressed broadly in the ureteric epithelium, cap mesenchyme and nephron derivatives (Dudley et al, 1997). Bmp7 signaling promotes the maintenance and proliferation of progenitors through a JNK mechanism (Blank et al, 2009; Tomita et al, 2013), and progenitor commitment through Smad-directed processes (Brown et al 2013). …”

Epigenetics in acute kidney injury

“…Marumo et al also found that ischemia/reperfusion of the mouse kidney induced a transient decrease in histone acetylation in the ischemic period, and subsequently down-regulation of HDAC5 during the recovery phase, resulting in histone re-acetylation and induction of bone morphogenetic protein-7 (BMP7) in proximal tubular cells [21]*. BMP7 is a key developmental factor in nephron formation during kidney development and is required for the proliferation and repair of the tubular cells after ischemia [22,23]. Thus, HDAC5 inhibition may serve as a potential therapeutic strategy for accelerating regeneration of the injured kidney.…”

BMP-7 Signaling and its Critical Roles in Kidney Development, the Responses to Renal Injury, and Chronic Kidney Disease

“…As mentioned previously, Bmp7 À/À mice die shortly after birth due to a premature cessation of nephrogenesis (Dudley et al, 1995;Luo et al, 1995). More recently, it was shown in a conditional Bmp-7 knockout model that even loss of BMP-7 expression at time points late in gestation lead to deficits in nephron endowment (Tomita et al, 2013).…”