Susan P. Bagby

Obesity-initiated metabolic syndrome and the kidney: A recipe for chronic kidney disease?

Metabolic syndrome, originally described in 1988 as “syndrome X” by Reaven et al. ([1][1]), has evolved in our collective thinking from a vague association of common chronic disease states to a formally defined cluster of clinical traits with adverse impact on cardiovascular risk ([2][2]). The

Developmental Antecedents of Cardiovascular Disease: A Historical Perspective

Knowledge of the fetal antecedents of cardiovascular disease has increased rapidly since the association between low birth weight and the disease was demonstrated 20 yr ago. It now is known that individuals who had low birth weight or who were thin or short at birth are at increased risk for both cardiovascular disease and type 2 diabetes. This has been shown in studies in different countries and cannot be explained by confounding variables. Through clinical and animal studies, the biologic processes that underlie the epidemiologic associations and how their effects are modified by postnatal growth and by living conditions in childhood and adult life are beginning to be understood. One such process is altered renal development, with reduced nephron numbers, which may initiate hypertension.

Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of (125)I-AngI to (125)I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 +/- 2.9 fmol AngII/min/ micro g protein with a mean maximal conversion of 55% +/- 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.

Quality of life in autosomal dominant polycystic kidney disease patients not yet on dialysis

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD) is an inherited progressive disorder associated with significant pain and discomfort affecting quality of life. This study determined the impact of pain medication use and other clinical, biochemical and genetic characteristics on the physical and mental well being of predialysis ADPKD patients using the Short Form 36 (SF-36) questionnaire. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The authors prospectively evaluated ADPKD patients in the Cohort Study, funded by the Polycystic Kidney Disease Foundation. Data on clinical, biochemical, and radiologic variables were collected in patients who were given the Short Form-36 questionnaire. Variables independently associated with the Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores were identified. RESULTS One hundred fifty-two patients had a mean PCS and MCS of 46.9 +/- 11.3 and 51.0 +/- 9.0, similar to the general population and better than the ESRD population. Eleven (7%) reported pain medication intake within 1 mo of evaluation and demonstrated lower PCS than those not taking pain medications. Patients with GFR >or= 80 ml/min/1.73 m(2) had greater PCS than those with GFR < 80 ml/min/1.73 m(2). Age, BMI, pulse pressure, pain medication use, and education level independently associate with PCS and account for 32% of the variability of the measurement. Pulse pressure correlated with MCS. CONCLUSIONS Predialysis ADPKD patients assess their quality of life similar to the general population. Age, BMI, pulse pressure, pain medication intake, and education level link to their physical well-being.

p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21.Methodsp21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay.ResultsWe show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis.ConclusionThe novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy.

Cardiovascular and Systemic Microvascular Effects of Anti-Vascular Endothelial Growth Factor Therapy for Cancer

OBJECTIVES This study sought to evaluate the contribution of microvascular functional rarefaction and changes in vascular mechanical properties to the development of hypertension and secondary ventricular remodeling that occurs with anti-vascular endothelial growth factor (VEGF) therapy. BACKGROUND Hypertension is a common side effect of VEGF inhibitors used in cancer medicine. METHODS Mice were treated for 5 weeks with an anti-murine VEGF-A monoclonal antibody, antibody plus ramipril, or sham treatment. Microvascular blood flow (MBF) and blood volume (MBV) were quantified by contrast-enhanced ultrasound in skeletal muscle, left ventricle (LV), and kidney. Echocardiography and invasive hemodynamics were used to assess ventricular function, dimensions and vascular mechanical properties. RESULTS Ambulatory blood pressure increased gradually over the first 3 weeks of anti-VEGF therapy. Compared with controls, anti-VEGF-treated mice had similar aortic elastic modulus and histological appearance, but a marked increase in arterial elastance, indicating increased afterload, and elevated plasma angiotensin II. Increased afterload in treated mice led to concentric LV remodeling and reduced stroke volume without impaired LV contractility determined by LV peak change in pressure over time (dp/dt) and the end-systolic dimension-pressure relation. Anti-VEGF therapy did not alter MBF or MBV in skeletal muscle, myocardium, or kidney; but did produce cortical mesangial glomerulosclerosis. Ramipril therapy almost entirely prevented the adverse hemodynamic effects, increased afterload, and LV remodeling in anti-VEGF-treated mice. CONCLUSIONS Neither reduced functional microvascular density nor major alterations in arterial mechanical properties are primary causes of hypertension during anti-VEGF therapy. Inhibition of VEGF leads to an afterload mismatch state, increased angiotensin II, and LV remodeling, which are all ameliorated by angiotensin-converting enzyme inhibition.

Developmental Origins of Renal Disease: Should Nephron Protection Begin at Birth?

That an adverse environment early in life— in utero or in the early postnatal period—can create vulnerability to chronic disease in later life is no longer a surprise. Following the lead of Barker and colleagues beginning in the late 1980s, a burgeoning literature now documents the increased risk of later-life hypertension (1), diabetes (2), coronary disease (3), and obesity (4) conferred by low birth weight, a surrogate for poor intrauterine growth. However, solid data documenting clinical relevance of the “developmental origins of disease” concept to the kidney have been slower to emerge. We know that the critical window of kidney development spans 9 to 35 wk gestational age (GA) (5), although the point of completion can vary from 32 to 35 wk (6,7). Nephrogenesis involves successive branching of the ingrowing ureteral bud, with new nephron units forming at branch tips via co-inductive crosstalk between the ureteral bud epithelium and surrounding undifferentiated mesenchyme. Of note, this process proceeds in concentric layers, such that newly forming nephrons are located in the outer layer, with the more mature nephron units occupying successively deeper layers. Fortunately, when growth rate is impaired during this fixed developmental window, the fetal kidney forms—not incomplete nephrons—but fewer layers of normal nephrons. Nonetheless, because no new nephrons form after 35 wk GA, nephron endowment is at that point fixed for life. Thus poor intrauterine growth during nephrogenesis may yield a nephron deficit as a permanent structural legacy. As in postnatal life, the developing fetal kidney is exquisitely sensitive to body size such that fetal kidney weight reflects body weight and—on the basis of careful studies in humans (8,9) and nonhuman primates (10)—grows by adding new nephrons. Recent stereologic studies of autopsied kidneys have shown that, in humans born at term, nephron number is in fact …

Angiotensin II Type 1 and 2 Receptors in Conduit Arteries of Normal Developing Microswine

Objective—To identify vascular cells capable of responding to angiotensin II (Ang II) generated in conduit arteries, we examined the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) in the thoracic aorta (TA) and abdominal aorta (AA) and branches in 90-day fetal, 3-week postnatal, and 6-month adult microswine. Methods and Results—By autoradiography (125I-[Sar1Ile8]-Ang II with or without AT1R- or AT2R-selective analogues or 125I - CGP 42112), there were striking rostrocaudal differences in (1) AT2R binding at all ages (prominent in AA wall and branches, sparse in TA wall and branches) and (2) a non-AT2R binding site for CGP 42112 (consistently evident in postnatal TA and branches but absent in AA and branches). Furthermore, patterns of AT2R distribution in infradiaphragmatic arteries were developmentally distinct. In fetal AAs, high-density AT2Rs occupied the inner 60% of the medial-endothelial wall. In postnatal AAs, AT2Rs were sparse in the medial-endothelial wall but prominent in a circumferential smooth muscle &agr;-actin–negative cell layer at the medial-adventitial border, occupying ≈20% to 25% of the AA cross-sectional area. AT1R density in the TA and AA medial-endothelial wall increased with age, whereas AT2R density decreased after birth. Conclusions—A novel AT2R-positive cell layer confined to postnatal infradiaphragmatic arteries physically links adventitial and medial layers, appears optimally positioned to transduce AT2R-dependent functions of local Ang II, and suggests that adventitial Ang II may elicit regionally distinct vascular responses.

Developmental Hypertension, Nephrogenesis, and Mother's Milk: Programming the Neonate

Compelling epidemiologic and experimental evidence indicates that early-life experiences shape risk for disease in later life. Infants who are born smaller, reflecting a slower growth trajectory in utero, experience higher incidences of hypertension, obesity, diabetes, and renal disease as adults (1). Birth weight is a crude surrogate for the broad spectrum of specific adverse events that may impair fetal growth in humans; therefore, experimental models have been developed to probe postnatal outcomes after specific interventions that are relevant to human pregnancy, including nutrient deficits and placental insufficiency (2). Attention continues to focus primarily on fetal growth, a period of biologic plasticity in which environmental insults can permanently “program” the fetus and thereby alter the postnatal phenotype by a number of different mechanisms. Impaired growth during critical periods of organ development may have an impact on disease risk by permanently reducing the number of functional units, for

Maternal malnutrition and placental insufficiency induce global downregulation of gene expression in fetal kidneys

Malnutrition during pregnancy causes intrauterine growth restriction and long-term changes in the offsprings physiology and metabolism. To explore molecular mechanisms by which the intrauterine environment conveys programming in fetal kidneys, an organ known to undergo substantial changes in many animal models of late gestational undernutrition, we used a microswine model of maternal protein restriction (MPR) in which sows were exposed to isocaloric low protein (LP) diet during late gestation/early lactation to encompass the bulk of nephrogenesis. To define general v. model-specific effects, we also used a sheep model of placental insufficiency. In kidneys from near-term fetal and neonatal microswine LP offspring, per cell levels of total RNA, poly(A)+ mRNA and transcripts of several randomly chosen housekeeping genes were significantly reduced compared to controls. Microarray analysis revealed only a few MPR-resistant genes that escape such downregulation. The ratio of histone modifications H3K4m3/H3K9m3 (active/silenced) was reduced at promoters of downregulated but not MPR-resistant genes suggesting that transcriptional suppression is the point of control. In juvenile offspring, on a normal diet from weaning, cellular RNA levels and histone mark patterns were recovered to near control levels, indicating that global repression of transcription is dependent on ongoing MPR. Importantly, cellular RNA content was also reduced in ovine fetal kidneys during placental insufficiency. These studies show that global repression of transcription may be a universal consequence of a poor intrauterine environment that contributes to fetal restriction.