Abstract
Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and β2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years. β2 (Arg16Gly, Gln27Glu)-adrenoceptor polymorphisms were determined. The subjects were stable in body weight and BP (<10%) for 5 years. High plasma NE was defined as ≥mean+1 SD at entry. Thirty-seven subjects had entry-high plasma NE and 182 were entry-normal. Entry-high plasma NE subjects had significantly greater total body fat mass and plasma NE and significantly lower creatinine clearance at entry and throughout the study. Increases in BMI, fat mass, BP, plasma NE, BUN, and creatinine, as well as the reduction in creatinine clearance in the 5 years, were significantly greater in entry-high NE subjects. These subjects had significantly higher frequencies of the Gly16 allele of β2-adrenoceptor polymorphisms. Throughout the study, subjects carrying the Gly16 allele had higher plasma NE, HOMA-IR, and fat mass, and significantly greater reductions in creatinine clearance. Plasma NE at entry was a determinant variable for changes in BUN, creatinine, and creatinine clearance over the 5-year period in multiple regression analysis. In conclusion, high plasma NE at entry, associated with the Gly16 allele of the β2-adrenoceptor polymorphisms, predict renal function deterioration (seen in elevations of BUN and creatinine and reduction of creatinine clearance) over a 5-year period accompanying further heightened sympathetic nerve activity and deterioration of insulin resistance.
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Arnlov J, Evans JC, Meigs JB, et al: Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals. The Framingham Heart Study. Circulation 2005; 112: 969–975.
White SL, Cass A, Atkins RC, Chadban SJ : Chronic kidney disease in the general population. Adv Chronic Dis 2005; 12: 5–13.
Hall JE, Jones DW, Kuo JJ, da Silva A, Tallam LS, Liu J : Impact of the obesity epidemic on hypertension and renal disease. Curr Hypertens Rep 2003; 5: 386–392.
Colditz GA, Willett WC, Rotnizky A, Manson JE : Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995; 122: 481–486.
Garrison RJ, Kannel WB, Stokes J, et al: Incidence and precursors of hypertension in young adults: the Framingham offspring study. Prev Med 1987; 16: 235–251.
Physical status : the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1995; 854: 1–452.
Tuck ML : The sympathetic nervous system in essential hypertension. Am Heart J 1986; 112: 877–886.
Grassi G, Dell'Oro R, Facchini A, Quarti-Trevano F, Bolla GB, Mancia G : Effect of central and peripheral body fat mass distribution on sympathetic and baroreflex function in obese normotensives. J Hypertens 2004; 22: 2363–2369.
Masuo K, Mikami H, Ogihara T, Tuck ML : Weight gain–induced blood pressure elevation. Hypertension 2000; 35: 1135–1140.
Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML : Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 2003; 42: 474–480.
Masuo K, Mikami H, Ogihara T, Tuck ML : Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in young, nonobese Japanese population. Am J Hypertens 1997; 10: 77–83.
Zoccali C, Mallamaci F, Parlongo S, et al: Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 2002; 105: 1354–1359.
Cui J, Hopper JL, Harrap SB : Gene and family environment explain correlations between blood pressure and body mass index. Hypertension 2002; 40: 7–12.
Masuo K, Mikami H, Ogihara T, Tuck ML : Familial hypertension, insulin, sympathetic activity, and blood pressure elevation. Hypertension 1998; 32: 96–100.
Masuo K, Mikami H, Ogihara T, Tuck ML : Familial obesity, sympathetic activation and blood pressure level. Blood Press 2001; 10: 199–204.
Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML : β2- and β3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years. Circulation 2005; 111: 3429–3434.
Pereira AC, Floriano MS, Mota GF, et al: β2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population. Hypertension 2003: 42 ( Part 2): 685–692.
Hahntow IN, Koopmans RP, Michel MC : The β2-adrenoceptor gene and hypertension: is it the promoter or the coding region or neither? J Hypertens 2006; 24: 1003–1007.
Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML : β2-Adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals. Am J Hypertens 2005; 18: 1009–1014.
Fournier A, Achard JM : Mnemotechnical note on the use of Cockroft creatinine clearance formula for the validation of a 24-h urine collection. Nephrol Dial Transplant 2000; 15: 1677–1678.
Ranade K, Change MS, Ting CT, et al: High-throughput genotyping with single nucleotide polymorphisms. Genome Res 2001; 11: 1262–1268.
Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML : Lys418Asn polymorphism of the α2-adrenoceptor gene relates to serum uric acid levels but not to insulin sensitivity. Hypertension 2005; 46: 1–7.
Manjunath G, Tighiouart H, Ibrahim H, et al: Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003; 41: 47–55.
Zoccali C, Mallamaci F, Tripepi G, et al, CREED investigators : Norepinephrine and concentric hypertrophy in patients with end-stage renal disease. Hypertension 2002; 40: 41–46.
Joles JA, Koomans HA : Causes and consequences of increased sympathetic activity in renal disease. Hypertension 2004; 43: 699–706.
Bulger RE, Burke TJ, Cronin RE, Schrier RW, Dabyan DC : Morphology of norepinephrine-induced acute renal failure in the dog. Anat Rec 1982; 214: 341–347.
Amann K, Koch A, Hofstetter J, et al: Glomerulosclerosis and progression: effect of sub-antihypertensive doses of alpha and beta blockers. Kidney Int 2001; 60: 1309–1323.
Erami C, Zhang H, Ho JG, French DM, Faber JE : α1-Adrenoceptor stimulation directly induces growth of vascular wall in vivo. Am J Physiol Heart Circ Physiol 2002; 283: H1577–H1587.
Henegar JR, Biyler SA, Henegar LK, Tyagi SC, Hall JE : Functional and structural changes in the kidney in the early stage of obesity. J Am Soc Nephrol 2001; 12: 1211–1217.
McGill HC Jr, McMahan CA : Starting earlier to prevent heart disease. JAMA 2003; 290: 2320–2322.
Esler M, Rumantir M, Wisener G, Kaye D, Hastings J, Lambert G : Sympathetic nervous system and insulin resistance from obesity to diabetes. Am J Hypertens 2001; 14: 304S–309S.
Agnani S, Vachharajani VT, Gupta R, Atray NK, Vaxhharajan TJ : Does treating obesity stabilize chronic kidney disease? BMC Nephrol 2005; 6: 7.
Rahmouni K, Morgan DA, Morgan GM, Mark AL, Haynes WG : Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes 2005; 54: 2012–2018.
Masuo K, Mikami H, Ogihara T, Tuck ML : Prevalence of hyperinsulinemia in young, nonobese Japanese men. J Hypertens 1997; 15: 157–165.
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Masuo, K., Katsuya, T., Sugimoto, K. et al. High Plasma Norepinephrine Levels Associated with β2-Adrenoceptor Polymorphisms Predict Future Renal Damage in Nonobese Normotensive Individuals. Hypertens Res 30, 503–511 (2007). https://doi.org/10.1291/hypres.30.503
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DOI: https://doi.org/10.1291/hypres.30.503