The National Institute of Diabetes & Digestive & Kidney Diseases

The overall goal of our research is to improve the understanding of the role of the kidneys in the maintenance of body fluid volume and arterial blood pressure. Specifically, we study the renal mechanisms responsible for the match between glomerular filtration of plasma and tubular salt and fluid reabsorption that is ultimately responsible for the precise balance between salt intake and excretion. One of the key mechanisms that mediates between renal absorption and filtration function is the so-called tubuloglomerular feedback, a regulatory pathway in which a measure of tubular reabsorptive capacity serves as the signal to alter glomerular filtration. This mechanism stabilizes the pressure in the glomerular capillary bed by adjusting vascular resistance, an adjustment that is of critical importance in preventing arterial blood pressure from damaging the glomerular capillary network. The vasomotion required to stabilize glomerular pressure and perfusion results from the regulated release of adenosine and its interaction with adenosine 1 receptors (A1AR) on the glomerular microvasculature. We perform most of our studies in mice since the ability to manipulate individual genes selectively greatly enhances the analytical power of our studies. In particular, the generation of A1AR-deficient mice has greatly aided progress in this area of research. A major source of adenosine is the extracellular dephosphorylation of released nucleotides, most notably ATP, but release of adenosine through nucleoside transporters cannot be excluded.

Adenosine is a ubiquitous nucleoside that is primarily generated from the dephosphorylation of nucleotides such as ATP, ADP, and AMP, and its interaction with widely expressed surface receptors causes numerous effects throughout the organism ranging from regulation of brain, cardiac and renal function to modulation of inflammation and cytotoxicity. While our main focus is the kidney, we are also studying the pleiotropic actions of adenosine exerted through A1AR activation using cre-lox techniques to achieve cell-specific deletions of A1AR in the brain, smooth muscle, brown fat and other tissues. In addition we have produced and are studying mice with transgenic overexpression of A1AR.

An additional area of interest is the circadian variability of cardiovascular and renal function. Like many functions in the body, mean arterial blood pressure undergoes regular daily variation with an elevation in the active phase (day time in humans, night time in mice) and a reduction in the inactive phase (night time in humans, day time in mice). In the presence of the external cue of daylight this variation is synchronized to the 24 hour cycle, but it persists in the absence of the external cue although with a cycle length that can be shorter or longer than 24 hours. Attenuation of the circadian blood pressure amplitude as manifested by a failure of blood pressure to fall in the inactive phase (so-called non-dipper status) has been recognized as an independent cardiovascular risk factor particularly in hypertension and diabetic kidney disease. While enormous progress has been made in understanding the basic neuronal processes that drive the central circadian biological clock, the mechanisms of coupling of clock genes in the suprachiasmatic nucleus with systemic responses such as peripheral blood pressure and renal salt excretion are poorly understood. By applying radiotelemetry to mice with defined gene defects we aim at defining the peripheral mechanisms responsible for generating the blood pressure rhythm. The final goal is to provide improved management of the deranged blood pressure rhythm in hypertension and other disease states.

Schnermann, J., J.N. Lorenz, and J.P. Briggs. Cardiorenal phenotype of the mouse: from loss of genome to gain of phenome. In: Molecular and Genetic Basis of Renal Disease, edited by D. Mount and D. Pollak, Saunders Elsevier, Philadelphia, pp. 15-39, 2008

Schnermann, J., J.P. Briggs. The Function of the Juxtaglomerular Apparatus: Control of Glomerular Hemodynamics and Renin Secretion. In: The Kidney: Physiology and Pathophysiology (4^th Edition), edited by R.J. Alpern and S.C. Hebert, Elsevier, Burlington-San Diego-London, 589-626, 2008

Kim, S.M., C. Eisner, R. Faulhaber-Walter, D. Mizel, S.M. Wall, J.P. Briggs, J. Schnermann. Salt sensitivity of blood pressure in NKCC1-deficient mice. Am. J. Physiol. Renal Physiol. 295:F1230-1238, 2008

Kim S.M., Y. Huang, Y. Qin, D. Mizel, J.B. Schnermann, J. Briggs. Persistence of circadian variation in arterial blood pressure in β1/β2-adrenergic receptor-deficient mice. Am J Physiol Regul Integr Comp Physiol. 294:R427-R434, 2008

Castrop H., J. Schnermann. Isoforms of the renal Na/K/2Cl cotransporter NKCC2: Expression and Functional Significance. Am. J. Physiol. Renal Physiol. 295:F859-866, 2008

Schnermann, J., J.P. Briggs . Tubuloglomerular Feedback – Mechanistic Insights from Gene-Manipulated Mice. Kidney Int. 74:418-426, 2008

Oppermann, M., D. J. Friedman, R. Faulhaber-Walter, D. Mizel, H. Castrop, K. Enjyoji, S. C. Robson, J. Schnermann. Tubuloglomerular Feedback and Renin Secretion in NTPDase1/CD39-Deficient Mice. Am. J. Physiol. Renal Physiol. 294:F965-F970, 2008

Faulhaber-Walter R., L. Chen, M. Oppermann, S. M. Kim, Y. Huang, N. Hiramatsu, D. Mizel, H. Kajiyama, P. Zerfas, J. P. Briggs, J. B. Kopp, J. Schnermann. Lack of Adenosine 1 receptors augments diabetic hyperfiltration and glomerular injury. J. Am. Soc. Nephrol. 19:722-730, 2008

Oppermann M., D. Mizel , S.M. Kim, L. Chen, R. Faulhaber-Walter, Y. Huang, C. Li, C. Deng, J. Briggs, J. Schnermann, H. Castrop. Renal function in mice with targeted disruption of the A-isoform of the Na/K/2Cl cotransporter NKCC2. J. Am. Soc. Nephrol. 18:440-448, 2007

Chen, L., S. M. Kim, M. Oppermann, R. Faulhaber-Walter, Y. Huang, D. Mizel, M. Chen, M.L. Sequeira Lopez, L.S. Weinstein, R.A. Gomez, J.P. Briggs, J. Schnermann. Regulation of Renin in Mice with Cre Recombinase-Mediated Deletion of G protein Gsin Juxtaglomerular Cells. Am. J. Physiol. Renal Physiol. 292:F27-F37, 2007

Kim S.M., L. Chen, D. Mizel, Y.G. Huang, J.P. Briggs, J. Schnermann. Low Plasma Renin and Reduced Renin Secretory Responses to Acute Stimuli in Conscious COX-2-Deficient Mice. Am. J. Physiol. Renal Physiol. 292:F415-F422, 2007

Hashimoto S Huang Y Mizel D Briggs J Schnermann J Compensation of proximal tubule malabsorption in AQP1-deficient mice without TGF-mediated reduction of GFR. Acta Physiol Scand (181): 455-62, 2004. [Full Text/Abstract]

Castrop H Huang Y Hashimoto S Mizel D Hansen P Theilig F Bachmann S Deng C Briggs J Schnermann J Impairment of tubuloglomerular feedback regulation of GFR in ecto-5''-nucleotidase/CD73-deficient mice. J Clin Invest (114): 634-42, 2004. [Full Text/Abstract]

Castrop H Schweda F Mizel D Huang Y Briggs J Kurtz A Schnermann J Permissive role of nitric oxide in macula densa control of renin secretion. Am J Physiol Renal Physiol (286): F848-57, 2004. [Full Text/Abstract]

Hansen PB Castrop H Briggs J Schnermann J Adenosine induces vasoconstriction through Gi-dependent activation of phospholipase C in isolated perfused afferent arterioles of mice. J Am Soc Nephrol (14): 2457-65, 2003. [Full Text/Abstract]

Schnermann J Homer W. Smith Award lecture. The juxtaglomerular apparatus: from anatomical peculiarity to physiological relevance. J Am Soc Nephrol (14): 1681-94, 2003. [Full Text/Abstract]

Schnermann J Levine DZ Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide. Annu Rev Physiol (65): 501-29, 2003. [Full Text/Abstract]

Hansen PB Schnermann J Vasoconstrictor and vasodilator effects of adenosine in the kidney. Am J Physiol Renal Physiol (285): F590-9, 2003. [Full Text/Abstract]

Sun D Samuelson LC Yang T Huang Y Paliege A Saunders T Briggs J Schnermann J Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci U S A (98): 9983-8, 2001. [Full Text/Abstract]

Schnermann J Sodium transport deficiency and sodium balance in gene-targeted mice. Acta Physiol Scand (173): 59-66, 2001. [Full Text/Abstract]

Yang T Park JM Arend L Huang Y Topaloglu R Pasumarthy A Praetorius H Spring K Briggs JP Schnermann J Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. J Biol Chem (275): 37922-9, 2000. [Full Text/Abstract]

Vallon V Verkman AS Schnermann J Luminal hypotonicity in proximal tubules of aquaporin-1-knockout mice. Am J Physiol Renal Physiol (278): F1030-3, 2000. [Full Text/Abstract]

Yang T Huang Y Heasley LE Berl T Schnermann JB Briggs JP MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. J Biol Chem (275): 23281-6, 2000. [Full Text/Abstract]

Meneton P Ichikawa I Inagami T Schnermann J Renal physiology of the mouse. Am J Physiol Renal Physiol (278): F339-51, 2000. [Full Text/Abstract]

Yang T Endo Y Huang YG Smart A Briggs JP Schnermann J Renin expression in COX-2-knockout mice on normal or low-salt diets. Am J Physiol Renal Physiol (279): F819-25, 2000. [Full Text/Abstract]

Park JM Schnermann JB Briggs JP Cyclooxygenase-2. A key regulator of bladder prostaglandin formation. Adv Exp Med Biol (462): 171-81, 1999. [Full Text/Abstract]

Yang T Sun D Huang YG Smart A Briggs JP Schnermann JB Differential regulation of COX-2 expression in the kidney by lipopolysaccharide: role of CD14. Am J Physiol (277): F10-6, 1999. [Full Text/Abstract]

Traynor TR Smart A Briggs JP Schnermann J Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2. Am J Physiol (277): F706-10, 1999. [Full Text/Abstract]

Schnermann J Chou CL Ma T Traynor T Knepper MA Verkman AS Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc Natl Acad Sci U S A (95): 9660-4, 1998. [Full Text/Abstract]

Schnermann J Juxtaglomerular cell complex in the regulation of renal salt excretion. Am J Physiol (274): R263-79, 1998. [Full Text/Abstract]

Briggs JP, Schnermann J. Control of renin release and glomerular vascular tone by the juxtaglomerular apparatus. Hypertension(2nd ed): 1359-1383, 1995.