Acid-Base Imbalance; Cell Membrane Permeability; Hyperoxaluria; Urinary Tract Physiological Phenomena; Water-Electrolyte Imbalance; Nephrolithiasis; Cell Physiological Processes
Cellular & Molecular Physiology: Epithelial Transport of Ions and Solutes | Membrane Proteins - Pumps and Transporters | Physiology of Human Disease
The general goal of our research is to understand how the kidney regulates the composition of the urine, especially as needed to maintain the salt (NaCl) and acid-base balance of the body. To eliminate waste products from the body, the kidney filters gigantic quantities of the plasma (over 160 quarts per day) resulting in the flow of huge quantities of water, NaCl and the base bicarbonate through the renal tubules. The first portion of each renal tubule is called the proximal tubule, and the proximal tubules are collectively responsible for reabsorbing the vast majority of the filtered NaCl, bicarbonate and water, and secreting acid in the form of ammonium ions.
Our lab has specifically focused on identifying the proteins involved in mediating the transport of bicarbonate, NaCl and ammonium in the proximal tubule. We found that “knockout” mice lacking one of these transport proteins have a high incidence of calcium oxalate urinary stones, the same type that is most common in human patients with kidney stones. We showed that the cause of the calcium oxalate kidney stones is a very high concentration of oxalate in the urine. We found that this kidney transport protein also plays a very crucial role in the intestine, where it secretes oxalate and thereby limits how much of ingested oxalate is absorbed and then excreted in the urine. Based on this discovery, our laboratory has been devoting increasing effort to understanding the role of transporters in governing oxalate homeostasis and excretion. We have also been studying mechanisms by which oxalate crystals induce inflammation and thereby cause damage to the kidney and other tissues.
Extensive Research Description
Our general goal is to characterize the mechanisms regulating sodium, acid-base, and anion excretion by the kidney. Our work is primarily focused on membrane transport proteins mediating ion exchange, namely NHE isoforms mediating Na+-H+ exchange, and SLC26 isoforms mediating anion exchange. One approach involves the generation of isoform- and phospho-specific polyclonal and monoclonal antibodies to identify the cellular and subcellular sites of expression of ion exchangers in the kidney and other tissues, and to study their regulation. A complementary approach uses mice with targeted gene disruption to elucidate the physiological roles of ion exchangers and associated proteins under in vivo conditions. For example, work with mice lacking anion exchanger Slc26a6, which can function as an oxalate transporter, revealed a phenotype of calcium oxalate kidney stones. This finding in turn has motivated studies on the mechanisms and regulation of oxalate transporters and their roles in oxalate homeostasis, urolithiasis, and crystal-induced inflammation and kidney disease.
- Regulation of Na+-H+ exchanger NHE3 in the proximal tubule, a process important for controlling the salt, fluid, and acid-base balance of the body.
- Roles of SLC26 anion exchangers in directly and indirectly governing urinary oxalate excretion, a urinary constituent that is very important for kidney stone formation.
- Mechanisms amd roles of oxalate crystal deposition in inducing inflammation and causing kidney failure.
- Thomson, R.B., Thomson, C.L., and Aronson, P.S. N-glycosylation critically regulates function of oxalate transporter SLC26A6. Am. J. Physiol. in press, 2017.
- Knauf, F., Thomson, R.B., Heneghan, J.F., Jiang, Z., Adebamiro, A., Thomson, C.L., Barone, C., Asplin, J.R., Egan, M.E., Alper. S.L., and Aronson, P.S. Loss of CFTR impairs intestinal oxalate secretion. J. Am. Soc. Nephrol., in press, 2016.
- Mulay, S.R., Eberhard, J.N., Pfann, V., Marschner, J.A., Darisipudi, M.N., Daniel, C., Romoli, S., Desai, J., Grigorescu, M., Kumar, S.V., Rathkolb, B., Wolf, E., Hrabě de Angelis, M., Bäuerle, T., Dietel, B., Wagner, C.A., Amann, K., Eckardt, K.U., Aronson, P.S., Anders, H.J., and Knauf, F. Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice. Am. J. Physiol. in press, 2016.
- Ermer, T., Eckardt, K.U., Aronson, P.S., and Knauf, F. Oxalate, inflammasome, and progression of kidney disease. Curr. Opin. Nephrol. Hypertens. 25:363-371, 2016.
- Chen, T., Kocinsky, H.S., Cha, B., Murtazina, R., Yang, J., Tse, C.M., Singh, V., Cole, R., Aronson, P.S., deJonge, H., Sarker, R., and Donowitz, M. Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: identification of a multifunctional phosphorylation site. J. Biol. Chem. 290:1952-1965, 2015.
- Knauf, F., Asplin, J.R., Granja, I., Schmidt, I.M., Moeckel, G., David, R., Flavell, R.A., and Aronson, P.S. NALP3-mediated inflammation is the principal cause of progressive renal failure in oxalate nephropathy. Kidney Int. 84:895-901, 2013
- Hayashi, H., Tamura, A., Krishnan, D., Tsukita, S., Suzuki, Y., Kocinsky, H.S., Aronson, P.S., Orlowski, J., Grinstein, S., and Alexander, R.T. Ezrin is required for the functional regulation of the epithelial sodium proton exchanger, NHE3. PLoS One 8:e55623, 2013
- Ko, N., Knauf, F., Jiang, Z., Markovich, D., and Aronson, P.S. Sat1 is dispensable for active oxalate secretion in mouse duodenum. Am. J. Physiol. 303:C52-C57, 2012.
- Hassan, H.A., Cheng, M., and Aronson, P.S. Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells. Am. J. Physiol. 302:C46-C58, 2012.
- Knauf, F., Ko, N., Jiang, Z., Robertson, W.G., Van Itallie, C.M., Anderson, J.M., and Aronson, P.S. Net intestinal transport of oxalate reflects passive absorption and SLC26A6-mediated secretion. J. Am. Soc. Nephrol. 22:2247-2255, 2011.
- Kocinsky HS, Dynia DW, Wang T, Aronson PS. NHE3 phosphorylation at serines 552 and 605 does not directly affect NHE3 activity. Am J Physiol, 293:F212-8, 2007.
- Jiang Z, Asplin JR, Evan AP, Rajendran VM, Velazquez H, Nottoli TP, Binder HJ, Aronson PS. Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet, 38:474-8, 2006.