Ion Alex Bobulescu, M.D.
Molecular mechanisms of kidney injury and chronic kidney disease; Renal lipid metabolism and lipotoxicity; Gut microbiota and the kidney; Proximal tubule ion transport; Renal handling and (patho)physiologic roles of uric acid; Urinary proteins as research and diagnostic biomarkers.
Role of renal lipids and gut microbiota in obesity-related kidney disease
This project received funding from the National Institutes of Health to elucidate the mechanisms linking obesity, the gut microbiota, acid-base homeostasis, renal lipid abnormalities, and chronic kidney disease. Obesity increases the risk of chronic kidney disease (CKD), and is associated with accelerated CKD progression, but the pathogenic mechanisms linking obesity to CKD are incompletely understood. Based on our published and preliminary data, we postulate that (1) Excess supply of free fatty acids (FFA) to the kidney in obesity leads to renal triglyceride accumulation (steatosis) and lipotoxicity, which in turn is a key molecular mechanism underpinning chronic kidney disease; (2) Increased excretion of dietary and metabolic acid by the kidney in obesity mandates increased ammoniagenesis from glutamine in the proximal tubule, which in turn inhibits renal β-oxidation of FFA, directs fatty acids to non-oxidative metabolic pathways, and exacerbates renal steatosis and lipotoxicity; (3) In addition to increases in dietary and metabolic acid, obesity is associated with a diet-independent increase in acid production in the gut due to specific changes in the gut microbiota, which contributes to increased renal acid excretion, and further aggravates renal steatosis and lipotoxicity. These hypotheses are being tested using a combination of established and innovative techniques, from investigation of biochemical pathways in cultured cells to translational research.
Uric acid in health and disease
Uric acid has been implicated in a number of human conditions including kidney disease, kidney stones, hypertension and diabetes. We have demonstrated that uric acid stone formation in type 2 diabetes is attributable to a blunted renal ammoniagenic response to acid loading. We have also shown that blunted ammoniagenesis is at least in part due to impaired activity and regulation of the renal proximal tubule sodium-proton exchanger NHE3. Future studies aim to elucidate the molecular mechanisms underpinning these defects.
- Park SK, Rosenthal TR, Williams JS, Shelton JM, Takahashi M, Zhang S, Bobulescu IA. Metabolic and cardiovascular effects of chronic mild hyperuricemia in rodents. J Investig Med. 2018 Oct;66(7):1037-1044.
- Pathare G, Dhayat N, Mohebbi N, Wagner C, Bobulescu IA, Moe OW, Fuster DG. Acid and alkali loading cause acute changes in the B1 but not B2 subunit of V-ATPase in urinary exosomes. Kidney Int. 2018 Apr;93(4):871-880.
- Hu MC, Bobulescu IA, Quiñones H, Gisler SM, Moe OW. Dopamine reduces cell surface Na+/H+ exchanger-3 (NHE3) protein by decreasing NHE3 exocytosis and cell membrane recycling. Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F1018-F1025.
- Rutkowski JM, Pastor J, Sun K, Park SK, Bobulescu IA, Chen CT, Moe OW, Scherer PE. Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression. Kidney Int. 2017 Feb;91(2):324-337.
- Yokoo T, Clark HR, Pedrosa I, Yuan Q, Dimitrov I, Zhang Y, Lingvay I, Beg MS, Bobulescu IA. Quantification of renal steatosis in type II diabetes mellitus using dixon-based MRI. J Magn Reson Imaging. 2016 Nov;44(5):1312-1319.
- Zhang D*, Bobulescu IA*, Maalouf NM, Adams-Huet B, Poindexter J, Park S, Wei F, Chen C, Moe OW, Sakhaee K. Relationship Between Serum Uric Acid and Bone Mineral Density in the General Population and in Rats with Experimental Hyperuricemia. J Bone Miner Res. 2015 Jun; 30(6):992-9. (*equal contribution by first two authors)
- Bobulescu IA, Lotan Y, Zhang J, Rosenthal TR, Rogers JT, Adams-Huet B, Sakhaee K, Moe OW. Triglycerides in the Human Kidney Cortex: Relationship with Body Size. PLOS ONE 2014 Aug; 29;9(8):e101285.
- Smith CR, Poindexter JR, Meegan JM, Bobulescu IA, Jensen ED, Venn-Watson S, Sakhaee K. Pathophysiological and physicochemical basis of ammonium urate stone formation in dolphins. J Urol. 2014 Jul;192(1):260-266.
- Bobulescu IA, Maalouf NM, Capolongo G, Adams-Huet B, Rosenthal TR, Moe OW, Sakhaee K. Acute acid loading unmasks the renal ammonium excretion defect of idiopathic uric acid nephrolithiasis. Am J Physiol Renal Physiol. 2013 Nov;305(10):F1498-503.
- Bobulescu IA, Moe OW. Renal transport of uric acid: Evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012 Nov; 19(6):358-371.
- Bobulescu IA, Quiñones H, Gisler SM, Di Sole F, Shi M, Hu MC, Zhang J, Fuster DG, Wright N, Mumby M, Moe OW. Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: Role of Protein Phosphatase 2A. Am J Physiol Renal Physiol. 2010 Apr; 298:F1205‐F1213
- Bobulescu IA. Renal lipid metabolism and lipotoxicity. Curr Opin Nephrol Hypertens. 2010 Jul;19(4):393‐402.
- Bobulescu IA, Dubree M, Zhang J, McLeroy P, Moe OW. Reduction of renal triglyceride accumulation: Effects on proximal tubule Na+/H+ exchange and urinary acidification. Am J Physiol Renal Physiol. 2009 Nov; 297(5):F1419‐26.
- Bobulescu IA, Moe OW. Luminal Na+/H+ exchange in the proximal tubule. Pflugers Arch. 2009 May;458(1):5‐21.
- Bobulescu IA, Dubree M, Zhang J, McLeroy P, Moe OW. Effect of renal lipid accumulation on proximal tubule Na+/H+ exchange and ammonium secretion. Am J Physiol Renal Physiol. 2008 Jun; 294(6):F1315‐F1322.
- Zhang J*, Bobulescu IA*, Goyal S, Aronson PS, Baum MG, Moe OW. Characterization of Na+/H+ exchanger NHE8 in cultured renal epithelial cells. Am J Physiol Renal Physiol. 2007 Sep; 293(3):F761‐F766. (*equal contribution by first two authors)
- Wang D, Hu J, Bobulescu IA, Quill TA, McLeroy P, Moe OW, Garbers DL. A sperm‐specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC). Proc Natl Acad Sci U S A. 2007 May 29; 104(22):9325‐9330.
- Bobulescu IA, Moe OW. Na+/H+ exchangers in renal regulation of acid‐base balance Semin Nephrol. 2006 Sep; 26(5):334‐344.
- Bobulescu IA, Dwarakanath V, Zou L, Zhang J, Baum M, Moe OW. Glucocorticoids acutely increase cell surface Na+/H+ exchanger‐3 (NHE3) by activation of NHE3 exocytosis. Am J Physiol Renal Physiol. 2005 Oct; 289(4):F685‐F691.
- Bobulescu IA, Di Sole F, Moe OW. Na+/H+ exchangers: physiology and link to hypertension and organ ischemia. Curr Opin Nephrol Hypertens. 2005 Sep; 14(5):485‐494.