Nephron Number in Patients with Primary Hypertension

Department of Pathology, University of Heidelberg, Heidelberg, Germany.
New England Journal of Medicine (Impact Factor: 55.87). 01/2003; 348(2):101-8. DOI: 10.1056/NEJMoa020549
Source: PubMed

ABSTRACT A diminished number of nephrons has been proposed as one of the factors contributing to the development of primary hypertension.
To test this hypothesis, we used a three-dimensional stereologic method to compare the number and volume of glomeruli in 10 middle-aged white patients (age range, 35 to 59 years) with a history of primary hypertension or left ventricular hypertrophy (or both) and renal arteriolar lesions with the number and volume in 10 normotensive subjects matched for sex, age, height, and weight. All 20 subjects had died in accidents.
Patients with hypertension had significantly fewer glomeruli per kidney than matched normotensive controls (median, 702,379 vs. 1,429,200). Patients with hypertension also had a significantly greater glomerular volume than did the controls (median, 6.50x10(-3) mm3 vs. 2.79x10(-3) mm3; P<0.001) but very few obsolescent glomeruli.
The data support the hypothesis that the number of nephrons is reduced in white patients with primary hypertension.

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    • "On the other hand, high doses of retinoic acid are teratogenic, generating either embryonic kidneys, which undergo apoptotic regression or cystic malformations (Tse et al., 2005). Perhaps variations in maternal diet partly explain not only the wide range of nephron numbers per kidney found in humans but also the differences in nephron number between normotensive individuals and those with essential hypertension (Keller et al., 2003). The pathogenesis of CAKUT is also clearly influenced by genetic factors. "
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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a broad range of disorders that result from abnormalities of the urinary collecting system, abnormal embryonic migration of the kidneys, or abnormal renal parenchyma development. These disorders are commonly found in humans, accounting for 20-30% of all genetic malformations diagnosed during the prenatal period. It has been estimated that CAKUT are responsible for 30-50% of all children with chronic renal disease worldwide and that some anomalies can predispose to adult-onset diseases, such as hypertension. Currently, there is much speculation regarding the pathogenesis of CAKUT. Common genetic background with variable penetrance plays a role in the development of the wide spectrum of CAKUT phenotypes. This review aims to summarize the possible mechanisms by which genes responsible for kidney and urinary tract morphogenesis might be implicated in the pathogenesis of CAKUT. Birth Defects Research (Part C), 2014. © 2014 Wiley Periodicals, Inc. Copyright © 2014 Wiley Periodicals, Inc.
    Birth Defects Research Part C Embryo Today Reviews 11/2014; 102(4). DOI:10.1002/bdrc.21084 · 2.63 Impact Factor
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    • "Although the process of nephrogenesis has been extensively studied, and our understanding of the molecular and cellular mechanisms that control the formation of a nephron is growing rapidly (Costantini and Kopan, 2010; Little and McMahon, 2012; Mugford et al., 2009), little is known about the mechanisms that determine the number of nephrons. This is a particularly important issue given the evidence that low nephron number is a risk factor for hypertension and chronic kidney disease (Benz et al., 2011; Hoy et al., 2006; Keller et al., 2003; Luyckx and Brenner, 2005; Schreuder, 2012). In this study, we first confirmed that Gdnf is expressed by the multipotent, self-renewing nephron progenitor cells during kidney development. "
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    ABSTRACT: Nephrons, the functional units of the kidney, develop from progenitor cells (cap mesenchyme [CM]) surrounding the epithelial ureteric bud (UB) tips. Reciprocal signaling between UB and CM induces nephrogenesis and UB branching. Although low nephron number is implicated in hypertension and renal disease, the mechanisms that determine nephron number are obscure. To test the importance of nephron progenitor cell number, we genetically ablated 40% of these cells, asking whether this would limit kidney size and nephron number or whether compensatory mechanisms would allow the developing organ to recover. The reduction in CM cell number decreased the rate of branching, which in turn allowed the number of CM cells per UB tip to normalize, revealing a self-correction mechanism. However, the retarded UB branching impaired kidney growth, leaving a permanent nephron deficit. Thus, the number of fetal nephron progenitor cells is an important determinant of nephron endowment, largely via its effect on UB branching.
    Cell Reports 03/2014; 7(1). DOI:10.1016/j.celrep.2014.02.033 · 8.36 Impact Factor
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    • "Thus, kidney organogenesis requires a balance between self-renewal and differentiation of the nephron progenitor cells to ensure the generation of sufficient numbers of nephrons (Little and McMahon, 2012). Premature depletion of progenitors during kidney development results in renal hypoplasia, a common cause of congenital kidney failure and a significant risk factor for hypertension in adults (Keller et al., 2003; Bertram et al., 2011). "
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    ABSTRACT: Mammalian kidney organogenesis involves reciprocal epithelial-mesenchymal interactions that drive iterative cycles of nephron formation. Recent studies have demonstrated that the Six2 transcription factor acts cell autonomously to maintain nephron progenitor cells, whereas canonical Wnt signaling induces nephron differentiation. How Six2 maintains the nephron progenitor cells against Wnt-directed commitment is not well understood, however. We report here that Six2 is required to maintain expression of Osr1, a homolog of the Drosophila odd-skipped zinc-finger transcription factor, in the undifferentiated cap mesenchyme. Tissue-specific inactivation of Osr1 in the cap mesenchyme caused premature depletion of nephron progenitor cells and severe renal hypoplasia. We show that Osr1 and Six2 act synergistically to prevent premature differentiation of the cap mesenchyme. Furthermore, although both Six2 and Osr1 could form protein interaction complexes with TCF proteins, Osr1, but not Six2, enhances TCF interaction with the Groucho family transcriptional co-repressors. Moreover, we demonstrate that loss of Osr1 results in β-catenin/TCF-mediated ectopic activation of Wnt4 enhancer-driven reporter gene expression in the undifferentiated nephron progenitor cells in vivo. Together, these data indicate that Osr1 plays crucial roles in Six2-dependent maintenance of nephron progenitors during mammalian nephrogenesis by stabilizing TCF-Groucho transcriptional repressor complexes to antagonize Wnt-directed nephrogenic differentiation.
    Development 03/2014; 141(7). DOI:10.1242/dev.103283 · 6.46 Impact Factor
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