Browsing by Author "Sparks, Matthew A"

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Open Access
Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.
(J Am Soc Nephrol, 2016-08) Zhang, Jiandong; Rudemiller, Nathan P; Patel, Mehul B; Wei, QingQing; Karlovich, Norah S; Jeffs, Alexander D; Wu, Min; Sparks, Matthew A; Privratsky, Jamie R; Herrera, Marcela; Gurley, Susan B; Nedospasov, Sergei A; Crowley, Steven D
Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-α is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-α production induced by cisplatin. Finally, disrupting TNF-α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-α levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.
Open Access
Complex Role for E-Prostanoid 4 Receptors in Hypertension.
(Journal of the American Heart Association, 2019-02) Herrera, Marcela; Yang, Ting; Sparks, Matthew A; Manning, Michael W; Koller, Beverly H; Coffman, Thomas M
Background Prostaglandin E2 ( PGE 2) is a major prostanoid with multiple actions that potentially affect blood pressure ( BP ). PGE 2 acts through 4 distinct E-prostanoid ( EP ) receptor isoforms: EP 1 to EP 4. The EP 4 receptor ( EP 4R) promotes PGE 2-dependent vasodilation, but its role in the pathogenesis of hypertension is not clear. Methods and Results To address this issue, we studied mice after temporal- and cell-specific deletion of EP 4R. First, using a mouse line with loss of EP 4 expression induced universally after birth, we confirm that EP 4R mediates a major portion of the acute vasodilatory effects of infused PGE 2. In addition, EP 4 contributes to control of resting BP , which was increased by 5±1 mm Hg in animals with generalized deficiency of this receptor. We also show that EP 4 is critical for limiting elevations in BP caused by high salt feeding and long-term infusion of angiotensin II . To more precisely identify the mechanism for these actions, we generated mice in which EP 4R loss is induced after birth and is limited to smooth muscle. In these mice, acute PGE 2-dependent vasodilation was attenuated, indicating that this response is mediated by EP 4R in vascular smooth muscle cells. However, absence of EP 4R only in this vascular compartment had a paradoxical effect of lowering resting BP , whereas the protective effect of EP 4R on limiting angiotensin II-dependent hypertension was unaffected. Conclusions Taken together, our findings support a complex role for EP 4R in regulation of BP and in hypertension, which appears to involve actions of the EP 4R in tissues beyond vascular smooth muscle cells.
Open Access
Pannexin 1 Channels Control the Hemodynamic Response to Hypoxia by Regulating O₂-Sensitive Extracellular ATP in Blood.
(American journal of physiology. Heart and circulatory physiology, 2021-01-15) Kirby, Brett S; Sparks, Matthew A; Lazarowski, Eduardo R; Lopez Domowicz, Denise A; Zhu, Hongmei; McMahon, Timothy J
Pannexin1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contributes to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to tissue metabolic demand. Male and female mice devoid of Panx1 (Panx1-/-) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1-/- erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1-/- (N=6) and WT (N=6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1-/- mice (-16±9% vs -2±8%; P<0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1-/- (N=6) vs. WT (N=6) basally, and increased in WT but not Panx1-/- mice during hypoxia (8±6% vs -10±13%; P<0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs -9% for Panx1-/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1-/- (N=6) vs WT mice (N=6) (P<0.05). Mean hypoxia-induced ATP export from RBCs from Panx1-/- mice (N=8) was 82% lower than from WT (N=8) ( P<0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood.
Open Access
Pulmonary Hypertension Subtypes and Mortality in CKD.
(American journal of kidney diseases : the official journal of the National Kidney Foundation, 2019-11-12) Edmonston, Daniel L; Parikh, Kishan S; Rajagopal, Sudarshan; Shaw, Linda K; Abraham, Dennis; Grabner, Alexander; Sparks, Matthew A; Wolf, Myles
RATIONALE & OBJECTIVE:Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. STUDY DESIGN:Observational retrospective cohort study. SETTING & PARTICIPANTS:We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. EXPOSURES:Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. OUTCOMES:All-cause mortality. ANALYTICAL APPROACH:Multivariable Cox proportional hazards analysis. RESULTS:In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). LIMITATIONS:The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. CONCLUSIONS:In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD.
Open Access
Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.
(Kidney Int, 2014-12) Malone, Andrew F; Phelan, Paul J; Hall, Gentzon; Cetincelik, Umran; Homstad, Alison; Alonso, Andrea S; Jiang, Ruiji; Lindsey, Thomas B; Wu, Guanghong; Sparks, Matthew A; Smith, Stephen R; Webb, Nicholas JA; Kalra, Philip A; Adeyemo, Adebowale A; Shaw, Andrey S; Conlon, Peter J; Jennette, J Charles; Howell, David N; Winn, Michelle P; Gbadegesin, Rasheed A
Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.