SGLT2 inhibition in a kidney with reduced nephron number: Modeling and analysis of solute transport and metabolism

American Journal of Physiology - Renal Physiology

Volumn 314, Issue 5, 2018, Pages F969-F984

  Layton, Anita T ^a   Vallon, Volker ^b,c  

^a DUKE UNIVERSITY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c VA SAN DIEGO HEALTHCARE SYSTEM   (United States)

Author keywords

Diabetes; Epithelial transport; Glucose; Hypoxia; Oxygen consumption; Remnant kidney; SGLT2 inhibitor; Sodium glucose cotransporter

Indexed keywords

GLUCOSE; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SODIUM ION; SGLT2 PROTEIN, RAT; SLC5A2 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 2;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL COUNT; CHRONIC KIDNEY FAILURE; CONTROLLED STUDY; DIABETES MELLITUS; DIURESIS; DOWN REGULATION; GLUCOSE BLOOD LEVEL; GLUCOSE URINE LEVEL; GLUCOSURIA; HEART FAILURE; HYPOXIA; KALIURESIS; KIDNEY METABOLISM; KIDNEY PROXIMAL TUBULE; MODEL; NATRIURESIS; NEPHRON CELL; NONHUMAN; PRIORITY JOURNAL; RAT; SODIUM EXCRETION; SOLUTE; ANIMAL; BIOLOGICAL MODEL; BLOOD PRESSURE; COMPUTER SIMULATION; DIABETIC NEPHROPATHY; DISEASE MODEL; DRUG EFFECT; METABOLISM; NEPHRECTOMY; NEPHRON; OXYGEN CONSUMPTION; PATHOLOGY; PATHOPHYSIOLOGY; PHARMACOLOGY; TIME FACTOR; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; BIOLOGICAL TRANSPORT; BLOOD GLUCOSE; BLOOD PRESSURE; COMPUTER SIMULATION; DIABETIC NEPHROPATHIES; DISEASE MODELS, ANIMAL; DIURESIS; MODELS, BIOLOGICAL; NATRIURESIS; NEPHRECTOMY; NEPHRONS; OXYGEN CONSUMPTION; RATS; RENAL INSUFFICIENCY, CHRONIC; SODIUM-GLUCOSE TRANSPORTER 2; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; TIME FACTORS;

EID: 85044426288     PISSN: 1931857X     EISSN: 15221466     Source Type: Journal    
DOI: 10.1152/ajprenal.00551.2017     Document Type: Article

References (50)

1. 2 consumption, NOS, and Na/H exchange in diabetic rat proximal tubules. Am J Physiol Renal Physiol 283: F286-F293, 2002. doi:10.1152/ajprenal.00330.2001.
2. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens 8: 262-275.e9, 2014. doi:10.1016/j.jash.2014.01.007.
3. Brezis M, Rosen S. Hypoxia of the renal medulla-its implications for disease. N Engl J Med 332: 647-655, 1995. doi:10.1056/NEJM199503093321006.
4. Briggs JP, Schnermann J. The tubuloglomerular feedback mechanism: functional and biochemical aspects. Annu Rev Physiol 49: 251-273, 1987. doi:10.1146/annurev.ph.49.030187.001343.
5. Carmines PK, Ohishi K, Ikenaga H. Functional impairment of renal afferent arteriolar voltage-gated calcium channels in rats with diabetes mellitus. J Clin Invest 98: 2564-2571, 1996. doi:10.1172/JCI119075.
6. Chen Y, Fry BC, Layton AT. Modeling glucose metabolism in the kidney. Bull Math Biol 78: 1318-1336, 2016. doi:10.1007/s11538-016-0188-7.
7. Cherney DZI, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129: 587-597, 2014. doi:10.1161/CIRCULATIONAHA.113.005081.
8. Du Z, Yan Q, Duan Y, Weinbaum S, Weinstein AM, Wang T. Axial flow modulates proximal tubule NHE3 and H-ATPase activities by changing microvillus bending moments. Am J Physiol Renal Physiol 290: F289-F296, 2006. doi:10.1152/ajprenal.00255.2005.
9. Foley RN, Collins AJ. End-stage renal disease in the United States: an update from the United States Renal Data System. J Am Soc Nephrol 18: 2644-2648, 2007. doi:10.1681/ASN.2007020220.
10. Futrakul N, Vongthavarawat V, Sirisalipotch S, Chairatanarat T, Futrakul P, Suwanwalaikorn S. Tubular dysfunction and hemodynamic alteration in normoalbuminuric type 2 diabetes. Clin Hemorheol Microcirc 32: 59-65, 2005.
11. Hayslett JP, Kashgarian M, Epstein FH. Functional correlates of compensatory renal hypertrophy. J Clin Invest 47: 774-782, 1968. doi:10.1172/JCI105772.
12. Inzucchi SE, Viscoli CM, Young LH, Furie KL, Gorman M, Lovejoy AM, Dagogo-Jack S, Ismail-Beigi F, Korytkowski MT, Pratley RE, Schwartz GG, Kernan WN; IRIS Trial Investigators. Response to Comment on Inzucchi et al. Pioglitazone prevents diabetes in patients with insulin resistance and cerebrovascular disease. Diabetes Care 2016; 39: 1684-1692. Diabetes Care 40: e47-e48, 2017. doi:10.2337/dci16-0048.
13. Kaufman JM, Siegel NJ, Hayslett JP. Functional and hemodynamic adaptation to progressive renal ablation. Circ Res 36: 286-293, 1975. doi:10.1161/01.RES.36.2.286.
14. Kim S, Heo NJ, Jung JY, Son M-J, Jang HR, Lee JW, Oh YK, Na KY, Joo KW, Han JS. Changes in the sodium and potassium transporters in the course of chronic renal failure. Nephron Physiol 115: p31-41, 2010. doi:10.1159/000314542.
15. Klahr S, Hamm LL, Hammerman MR, Mandel LJ. Renal metabolism: integrated responses. In: Handbook of Physiology, edited by Berliner RW. Oxford, UK: Oxford University Press, 1989.
16. Körner A, Eklöf A-C, Celsi G, Aperia A. Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes 43: 629-633, 1994. doi:10.2337/diab.43.5.629.
17. Layton AT. A mathematical model of the urine concentrating mechanism in the rat renal medulla. I. Formulation and base-case results. Am J Physiol Renal Physiol 300: F356-F371, 2011. doi:10.1152/ajprenal.00203.2010.
18. Layton AT. A mathematical model of the urine concentrating mechanism in the rat renal medulla. II. Functional implications of three-dimensional architecture. Am J Physiol Renal Physiol 300: F372-F384, 2011. doi:10.1152/ajprenal.00204.2010.
19. + cotransporter. Am J Physiol Renal Physiol 302: F591-F605, 2012. doi:10.1152/ajprenal.00263.2011.
20. Layton AT, Edwards A, Vallon V. Adaptive changes in GFR, tubular morphology, and transport in subtotal nephrectomized kidneys: modeling and analysis. Am J Physiol Renal Physiol 313: F199-F209, 2017. doi:10.1152/ajprenal.00018.2017.
21. + transport inhibitors. Am J Physiol Renal Physiol 311: F1217-F1229, 2016. doi:10.1152/ajprenal.00294.2016.
22. Layton AT, Vallon V. Cardiovascular benefits of SGLT 2 inhibition in diabetes and chronic kidney diseases. Acta Physiol 222: e13050, 2018. doi:10.1111/apha.13050.
23. Layton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am J Physiol Renal Physiol 308: F1343-F1357, 2015. doi:10.1152/ajprenal.00007.2015.
24. Layton AT, Vallon V, Edwards A. A computational model for simulating solute transport and oxygen consumption along the nephrons. Am J Physiol Renal Physiol 311: F1378-F1390, 2016. doi:10.1152/ajprenal.00293.2016.
25. Layton AT, Vallon V, Edwards A. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am J Physiol Renal Physiol 310: F1269-F1283, 2016. doi:10.1152/ajprenal.00543.2015.
26. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation 136: 1643-1658, 2017. doi:10.1161/CIRCULATIONAHA.117.030012.
27. Moss R, Layton AT. Dominant factors that govern pressure natriuresis in diuresis and antidiuresis: a mathematical model. Am J Physiol Renal Physiol 306: F952-F969, 2014. doi:10.1152/ajprenal.00500.2013.
28. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377: 644-657, 2017. doi:10.1056/NEJMoa1611925.
29. Neuhofer W, Beck FX. Cell survival in the hostile environment of the renal medulla. Annu Rev Physiol 67: 531-555, 2005. doi:10.1146/annurev.physiol.67.031103.154456.
30. O’Donnell MP, Kasiske BL, Daniels FX, Keane WF. Effects of nephron loss on glomerular hemodynamics and morphology in diabetic rats. Diabetes 35: 1011-1015, 1986. doi:10.2337/diab.35.9.1011.
31. Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens 8: 330-339, 2014. doi:10.1016/j.jash.2014.02.003.
32. 2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol 309: F227-F234, 2015. doi:10.1152/ajprenal.00689.2014.
33. Palm F, Cederberg J, Hansell P, Liss P, Carlsson PO. Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia 46: 1153-1160, 2003. doi:10.1007/s00125-003-1155-z.
34. Palm F, Hansell P, Ronquist G, Waldenström A, Liss P, Carlsson PO. Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats. Diabetologia 47: 1223-1231, 2004. doi:10.1007/s00125-004-1434-3.
35. Petrykiv S, Sjöström CD, Greasley PJ, Xu J, Persson F, Heerspink HJL. Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function. Clin J Am Soc Nephrol 12: 751-759, 2017. doi:10.2215/CJN.10180916.
36. − cotransporter isoforms. J Biol Chem 277: 11004-11012, 2002. doi:10.1074/jbc.M110442200.
37. Rasch R, Dørup J. Quantitative morphology of the rat kidney during diabetes mellitus and insulin treatment. Diabetologia 40: 802-809, 1997. doi:10.1007/s001250050752.
38. Rich PR. The molecular machinery of Keilin’s respiratory chain. Biochem Soc Trans 31: 1095-1105, 2003. doi:10.1042/bst0311095.
39. Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res 8: 844-847, 2016. doi:10.14740/jocmr2760w.
40. Thomas MC, Moran JL, Harjutsalo V, Thorn L, Wadén J, Saraheimo M, Tolonen N, Leiviskä J, Jula A, Forsblom C, Groop PH; FinnDiane Study Group. Hyperfiltration in type 1 diabetes: does it exist and does it matter for nephropathy? Diabetologia 55: 1505-1513, 2012. doi:10.1007/s00125-012-2485-5.
41. Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 302: R75-R83, 2012. doi:10.1152/ajpregu.00357.2011.
42. Vallon V, Blantz RC, Thomson S. Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats. Am J Physiol 269: F876-F883, 1995. doi:10.1152/ajprenal.1995.269.6.F876.
43. Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 306: F194-F204, 2014. doi:10.1152/ajprenal.00520.2013.
44. Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol 22: 104-112, 2011. doi:10.1681/ASN.2010030246.
45. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 10: 2569-2576, 1999.
46. Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, Cunard R, Sharma K, Thomson SC, Rieg T. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol 304: F156-F167, 2013. doi:10.1152/ajprenal.00409.2012.
47. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 375: 323-334, 2016. doi:10.1056/NEJMoa1515920.
48. Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George JT, Woerle HJ, Broedl UC, von Eynatten M, Zinman B. Empagliflozin and clinical outcomes in patients with type 2 diabetes, established cardiovascular disease, and chronic kidney disease. Circulation 137: 119-129, 2018. doi:10.1161/CIRCULATIONAHA.117.028268.
49. Weinstein AM, Weinbaum S, Duan Y, Du Z, Yan Q, Wang T. Flow-dependent transport in a mathematical model of rat proximal tubule. Am J Physiol Renal Physiol 292: F1164-F1181, 2007. doi:10.1152/ajprenal.00392.2006.
50. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117-2128, 2015. doi:10.1056/NEJMoa1504720.