Kathleen Hering-Smith, PhD
Director, Nephrology & Hypertension Core
Phone: (504) 554-5889
PhD: Tulane University, 2004
Urinary citrate is one of the most important inhibitors of calcium nephrolithiasis. Various studies estimate that 19-63% of individuals with calcium containing kidney stones have hypocitraturia as a contributing cause. Understanding the mechanisms of the regulation of citrate transport will hopefully lead to improved diagnosis of causes of hypocitraturia. Urinary citrate is an important inhibitor of calcium nephrolithiasis and is primarily determined by fractional reabsorption in the proximal tubule. The dicarboxylate transporter (NaDC1) is presumably the main mechanism of apical uptake of filtered citrate along the nephron. The most important physiologic regulator of urinary citrate excretion is acid-base status. Also urinary citrate increases as urinary calcium increases.
Studies will address the acute regulation of citrate transport by calcium, and chronic regulation of citrate transport by acid-base perturbations and hypokalemia. Using a newly characterized in vitro model of citrate transport, OK cells studied under particular conditions, citrate and dicarboxylate uptake are sensitive to extracellular calcium. These studies indicate that the OK cell citrate transport system is likely a novel citrate transporter. Recently another cell line of dicarboxylate transport was developed. Human retinal pigmented epithelial cells stably transfected with human NaDC1 (CUBS cells) are responsive to acid-base conditions in vitro and will therefore represent a powerful new model. Two hypotheses will be examined:
- Calcium acutely inhibits a novel citrate transport process in mammalian proximal tubule cells.
- Chronic regulation of proximal tubule transport of citrate is accomplished by redundant mechanisms including changes in NaDC1 protein production and insertion of pre-existing NaDC1 protein into the apical membrane from sub-apical vesicles.
The results of these studies will help delineate the calcium sensitive citrate transport process by demonstrating that the calcium sensitive citrate transport process is a novel transporter, not NaDC1, and determining the cellular mechanisms whereby extracellular calcium alters this citrate transport process. In addition, these results will determine the mechanisms of chronic regulation of citrate transport by acid-base perturbations and hypokalemia. To achieve this, three modes of regulation will be examined: transcriptional (or mRNA stability) regulation, regulation at the protein level, and regulation by trafficking of NaDC1 into and out of the apical membrane from sub-apical vesicles under conditions of metabolic acidosis and hypokalemia.
- Weibo Mao, MD -- Research Scientist.
- Joycelyn Coleman-Barnett, BS -- Medical Research Technician.
- Ryan Walker, BS -- Graduate Student.
- Nakhoul F, Nakhoul N, Dorman E, Berger L, Skorecki K, Magen D. Gitelman's syndrome: a pathophysiological and clinical update. Endocrine 41: 53-57, 2012.
- Abdulnour-Nakhoul S, Nakhoul HN, Kalliny MI, Gyftopoulos A, Rabon E, Doetjes R, Brown K, Nakhoul NL. Ion transport mechanisms linked to bicarbonate secretion in the esophageal submucosal glands. Am J Physiol Regul Integr Comp Physiol 301: R83-R96, 2011.
- Nakhoul N, Batuman V. Role of proximal tubules in the pathogenesis of kidney disease. Contrib Nephrol 169: 37-50, 2011.
- Sammour RN, Nakhoul FM, Levy AP, Miller-Lotan R, Nakhoul N, Awad HR, Gonen R, Ohel G. Haptoglobin phenotype in women with preeclampsia. Endocrine 38: 303-308, 2010.
- Nakhoul NL, Abdulnour-Nakhoul SM, Schmidt E, Doetjes R, Rabon E, Hamm LL. pH sensitivity of ammonium transport by Rhbg. Am J Physiol Cell Physiol 299: C1386-C1397, 2010.
- Nakhoul NL, Abdulnour-Nakhoul SM, Boulpaep EL, Rabon E, Schmidt E, Hamm LL. Substrate specificity of Rhbg: ammonium and methyl ammonium transport. Am J Physiol Cell Physiol 299: C695-C705, 2010.
Recent Publications: A PubMed listing of research publications for Kathleen Hering-Smith, Ph.D.
Tulane University School of Medicine
Department of Medicine