Education & Training
- M.D.,Case Western Reserve University- 1998
- B.S., University of Michigan-1993
Research Interest Summary
Potassium is the most abundant intracellular cation and is absolutely necessary for existence, as it participates in critical biological processes, including neuronal and cardiac function, and in the control of cell volume and systemic blood pressure. However, since even slight fluctuations of extracellular potassium outside of the normal range can be lethal, the ingestion of a dietary potassium load presents a daily challenge for mammals. The kidney plays a critical role in the regulation of total body potassium balance. My laboratory seeks to understand how the kidney carries out this process at the molecular level. Our work is focused on the WNK-SPAK/OSR1 pathway, a network of serine-threonine kinases that function as a molecular switch that drives a kidney’s decision to reabsorb or eliminate K+. We employ a molecule-to-organism approach that incorporates biochemistry, proteomics, molecular biology, gene editing, high resolution fixed and live cell imaging, and whole animal physiology to understand how signals in the kidney function during health and disease.
Our efforts to understand how WNK kinases work have prompted us to analyze how they have evolved over time. These ongoing studies have revealed novel mechanisms that control their activity, ranging from an ancient and unique role as intracellular chloride sensors, to their ability to organize into membraneless condensates in response to ionic stress. Our team is unraveling how these fundamental properties of the WNK signaling pathway are necessary for basic cellular function, and for life in general.
Boyd-Shiwarski CR, Shiwarski DJ, Roy A, Nkashama LJ, Namboodiri HN, Xie J, McClain KL, Marciszyn A, Kleyman TR, Tan RJ, Stolz DB, Puthenveedu MA, Huang CL, Subramanya AR. Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent. Mol Biol Cell 2018 Feb 15;29(4):499-509. Epub 2017 Dec 13. PMID: 29237822.
Boyd-Shiwarski CR and Subramanya AR. The Renal Response to Potassium Stress: Integrating Past with Present. Curr Op Neph Hypertens 2017 Sep;26(5):411-418. PMID:28614118
Al-Qusairi L, Basquin D, Roy A, Rajamram RD, Maillard M, Subramanya AR, Staub O. Renal tubular ubiquitin protein ligase NEDD4-2 is required for renal adaptation during long-term potassium depletion. J Am Soc Nephrol. 2017 Aug;28(8):2431-2442. Epub 2017 Mar 13. PMID: 2829184.
Roy A, Al-Qusairi L, Donnelly BF, Ronzaud C, Marciszyn AL, Gong F, Chang YPC, Butterworth MB, Pastor-Soler NM, Hallows KR, Staub O, Subramanya AR. Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action. J Clin Invest 2015. Epub 2015 Aug 4. PMID: 26241057
Research highlight in Nature Reviews Nephrology: Epub 2015 Aug 25. PMID: 26303779
Roy A, Goodman JH, Begum G, Donnelly BF, Pittman G, Weinman EJ, Sun D, Subramanya AR. Generation of WNK1 knockout cell lines by CRISPR/Cas-mediated genome editing. Am J Physiol Renal Physiol. 2015 Feb 15;308(4):F366-76. Epub 2014 Dec 4. PMID 25477473.