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


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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    • "Ali and colleagues recently demonstrated that Ang-(1-7) concentration and ACE2 activity in the renal cortex were reduced in high-sodium diet (HSD) induced HT and that this was reversed by C21 (AT2R selective agonist) treatment [Ali et al. 2015]. Reduced nephron numbers are also associated with essential HT and this finding may be partly attributable to enhanced Ang II generation [Brenner and Chertow, 1994; Keller et al. 2003]. "
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    ABSTRACT: The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling. © The Author(s), 2015.
    Therapeutic Advances in Cardiovascular Disease 08/2015; 9(4). DOI:10.1177/1753944715597623 · 2.13 Impact Factor
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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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