Sodium-Hydrogen Antiport, Cell Function and Susceptibility to Diabetic Nephropathy

  • Roberto Trevisan
  • Giancarlo Viberti


The annual incidence of diabetic nephropathy rises rapidly over the first 15–20 years of diabetes, but declines sharply afterward for longer disease duration [1]. This pattern of risk indicates that only a subset of diabetic patients are susceptible to renal damage and, indeed, clinical renal disease cumulatively develops in approximately 30% of insulin-dependent diabetic (IDDM) patients [2] and between 15 and 60% of non-insulin-dependent diabetic (NIDDM) patients, depending on their ethnic origin[3]. Familiar clustering of diabetic nephropathy has been shown both in IDDM [4] and NIDDM patients [5]. These findings are consistent with the possibility that genetic factors may explain the liability to or protection from renal disease of diabetic patients.


Diabetic Patient Diabetic Nephropathy Essential Hypertension Skin Fibroblast Intermediate Phenotype 
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  1. 1.
    Krolewski AS, Warram JH, Rand LI, Kahn CR. Epidemiologic approach to the etiology of type 1 diabetes mellitus and its complications. N Engl J Med 1987; 317:1390–1398.PubMedCrossRefGoogle Scholar
  2. 2.
    Andersen AR, Christiansen JS, Andersen JK, Kretner S, Deckert T. Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983; 25:496–501.PubMedCrossRefGoogle Scholar
  3. 3.
    Viberti GC, Walker JD, Pinto J.: Diabetic Nephropathy, m International Textbook of diabetes mellitus. Alberti KGMM, DeFronzo RA, Keen H, Zimmet P. eds. John Wiley & Sons Ltd. 1992; vol 2: 1267–1328.Google Scholar
  4. 4.
    Seaquist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989; 320:1161–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Petitt DJ, Saad MF, Bennett PH, Nelson RG, Knowler WC. Familial predisposition to renal disease in two generations of Pima Indians with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1990; 33:438–43.CrossRefGoogle Scholar
  6. 6.
    Microalbuminuria Collaborative Study group. Risk factors for development of microalbuminuria in insulin-dependent diabetic patients: a cohort study. Br Med J1993; 306: 1235–9.Google Scholar
  7. 7.
    Poulsen PL, Hansen KW, Mogensen CE. Ambulatory blood pressure in the transition from normo- to microalbuminuria; a longitudinal study in IDDM patients. Diabetologia 1993; 36 (Suppl. 1)A214.Google Scholar
  8. 8.
    Viberti GC, Keen H, Wiseman MJ. Raised blood pressure in parents of proteinuric insulin-dependent diabetic patients. Br Med J 1987; 295: 575–577.CrossRefGoogle Scholar
  9. 9.
    Earle K, Walker J, Hill C, Viberti GC. Familial clustering of cardiovascular disease in patients with insulin dependent diabetes and nephropathy. N Engl J Med 1992; 326:673–677.PubMedCrossRefGoogle Scholar
  10. 10.
    Williams RR, Hunt SC, Kuida H, Smith JB, Ash KO. Sodium-lithium countertransport in erythrocytes of hypertension prone families in Utah. Am J Epidemiol 1983; 118: 338–44.PubMedGoogle Scholar
  11. 11.
    Morgan DB, Steward AD, Davidson C. Relations between erythrocyte lithium efflux, blood pressure and family history of hypertension And cardiovascular disease. Studies in a factory workforce and hypertension clinic. J Hypertens 1986; 4: 609–615.PubMedCrossRefGoogle Scholar
  12. 12.
    Mangiti R, Bending JJ, Scott G, Li LK, Gupta A, Viberti GC. Increased sodium-lhhium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 1988; 318: 146–150.CrossRefGoogle Scholar
  13. 13.
    Jones SL, Trevisan R, Tariq T, Semplicini A, Mattoch M, Walker JD, Nosadini R, Viberti GC. Increased sodium-lithium countertransport activity in insulin-dependent diabetic patients with microalbuminuria. Hypertension 1990; 15: 570–575.PubMedCrossRefGoogle Scholar
  14. 14.
    Morocutti A, Barzon I, Solini A, Sambataro M, Cipollina MR, Velussi M, Duner E, Muollo B, Crepaldi G, Nosadini R. Poor metabolic control and predisposition to hypertension, rather than hypertension itself, are risk factors for nephropathy in type 2 diabetes. Acta Diabetol 1992; 29: 123–129.CrossRefGoogle Scholar
  15. 15.
    Trevisan R, Nosadini R, Fioretto P, Semplicini A, Donadon v, Doria A, Nicolosi G, Zanuttini D, Cipollina MR, Lusiani L, Avogaro A, Crepaldi G, Viberti GC. Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport. Kidney Int 1992; 41: 855–861.PubMedCrossRefGoogle Scholar
  16. 16.
    Walker JD, Tariq T, Viberti GC. Sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy and their parents. Br Med J 1990; 301: 635–8.CrossRefGoogle Scholar
  17. 17.
    Canessa M, Morgan K, Semplicini A. Genetic differences in lithium- sodium exchange and regulation of the sodium-hydrogen exchanger in essential hypertension. J Cardiovasc Pharmacol 1988; 12 (Suppl. 3): S92–S98).CrossRefGoogle Scholar
  18. 18.
    Seifter JL, Aronson PS. Properties and physiological roles of the plasma membrane sodium-hydrogen exchanger. J Clin Invest 1986; 78: 859–864.PubMedCrossRefGoogle Scholar
  19. 19.
    Sardet C, Franchi A, Pouyssegur J: Molecular cloning, primary structure, and expression of the human growth factor-activatable soii V, Garrido MC, Bomford J, Hodcaday TDR. Leucocyte Na+/H+ antiport activity in type 1 (insulindium-hydrogen antiporter. Cell 1989; 56: 271–280PubMedCrossRefGoogle Scholar
  20. 20.
    Ng LL, Simmons D, Frighi-dependent) diabetic patients with nephropathy. Diabetologia 1990; 33: 371–77.PubMedCrossRefGoogle Scholar
  21. 21.
    Ng LL, Dudley C, Bomford J, Hawley D. Leucocyte intracellular pH and Na+/H+ antiport activity in human hypertension. J Hypertens 1989; 7:471–475.PubMedCrossRefGoogle Scholar
  22. 22.
    Semplicini A, Mozzato MG, Samá B, Nosadini R, Fioretto P, Trevisan R, Pessina A, Crepaldi G, Dal Palù D. Sodium-hydrogen and lithium-sodium exchange in red cells of normotensive and hypertensive patients with insulin-dependent diabetes mellitus. Am J Hypertens 1989; 2: 174–77.PubMedGoogle Scholar
  23. 23.
    Trevisan R, Li LK, Messent J, Tariq T, Earle KA, Walker JD, Viberti GC. Na/H antiport activity and cell growth in cultured skin fibroblasts of IDDM patients with nephropathy. Diabetes 1992; 41:1239–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Davies JE, Ng LL, Kofoed-Enevoldsen A, Li LK, Earle A, Trevisan R, Viberti GC. Intracellular pH and Na+/H+ antiport activity of cultured skin fibroblasts from diabetics. Kidney Int 1992; 42: 1184–1190.PubMedCrossRefGoogle Scholar
  25. 25.
    Lurbe A, Fioretto P, Mauer M, LaPointe MS, Battle D. Growth phenotype of cultured skin fibroblasts from IDDM patients with and without nephropathy and overactivity of the Na/H antiporter. Kidney Int 1996; 50:1684–1693.PubMedCrossRefGoogle Scholar
  26. 26.
    Ng LL, Davies JE, Siczkowski M, Sweeney FP, Quinn PA, Krolewski B, Krolewski AS. Abnormal sodium-hydrogen antiporter phenotype and turnover of immortalized lymphoblasts from type 1 diabetic patients with nephropathy. J Clin Invest 1994; 93: 2750–57.PubMedCrossRefGoogle Scholar
  27. 27.
    Siczkowski M, Davies JE, Sweeney FP, Kofoed-Enevoldsen A, Ng LL. Na/H exchanger isoform-1 abundance in skin fibroblasts of type 1 diabetic patients with nephropathy. Metabolism 1995; 44: 791–795.PubMedCrossRefGoogle Scholar
  28. 28.
    Trevisan R, Fioretto P, Mauer SM, Duner E, Cipollina MR, Trevisan M, Barbosa J, Nosadini R. Concordance for sodium-hydrogen antiport activity in insulin-dependent diabetic sibling pairs. Diabetologia 1995; 38 (Suppl. 1): A230.Google Scholar
  29. 29.
    Trevisan R, Cipollina MR, Dimer E, Trevisan M, Nosadini R. Abnormal sodium hydrogen antiport activity in cultured fibroblasts from non-insulin-dependent diabetic patients with hypertension and microalbuminuria. Diabetologia 1996; 39:717–724.PubMedCrossRefGoogle Scholar
  30. 30.
    Ng LL, Simmons D, Frighi V, Garrido MC, Bomford J. effect of protein kinase C modulators on the leucocyte sodium-hydrogen antiport in type 1 diabetic subjects with albuminuria. Diabetologia 1990; 33: 278–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Sweeney FP, Siczkowski M, Davies JE, Quinn PA, McDonald J, Krolewski B, Krolewski AS, Ng LL. Phosphorylation and activity of Na /H exchanger isoform 1 of immortalized lymphoblasts in diabetic nephropathy. Diabetes 1995; 44:1180–85.PubMedCrossRefGoogle Scholar
  32. 32.
    Williams B, Howard RL. Glucose-induced changes in Na/H antiport activity and gene expression in cultured vascular smooth muscle cells: role of protein kinase C. J Clin Invest 1994; 93: 2623–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Davies JE, Siczkowski M, Sweeney FP, Quinn PA, Krolewski B, Krolewski AJ, Ng LL. Glucose-induced changes in turnover of Na+/H+ exchanger of immortalized lymphoblasts from type 1 diabetic patients with nephropathy. Diabetes 1995; 44:382–88.PubMedCrossRefGoogle Scholar
  34. 34.
    Berk BC, Vallega G, Muslin AJ, Gordon HM, Canessa M, Alexander RW. Spontaneously hypertensive rat vascular muscle cells in culture exhibit increased growth and Na/H exchange. J Clin Invest 1989; 83: 822–29.PubMedCrossRefGoogle Scholar
  35. 35.
    Guicheney P, Wauquier I, Paquet JU Meyer P. Enhanced response to growth factors and to angiotensin II of spontaneously hypertensive rat skin fibroblasts in culture. J Hypertens 1991; 9 (Suppl. 1): 23–28.PubMedGoogle Scholar
  36. 36.
    Rosskopt D, Fromter E, Siffert W. Hypertensive sodium-proton exchanger phenotype persists in immortalized lymphoblasts from essential hypertensive patients. J Clin Invest 1993; 92:2553–59.CrossRefGoogle Scholar
  37. 37.
    Strazzullo P, De Simone G, Celentano A, Iacone R, Ragone E, Pagano E, Tammaro P, Canessa M. Sodiul-hydrogen rchange and cardiac hypertrophy in patients with primary hypertension. J Hypertens 1991; 9 (Suppl. 6): S306–S307.CrossRefGoogle Scholar
  38. 38.
    Morocutti A, Earie KA, Sethi M, Piras G, Pal K, Richards D, Rodeman P, Viberti GC. Premature sensescence of skin fibroblasts from insulin-dependent diabetic patients with kidney disease. Kidney Int 1996; 50:250–256.PubMedCrossRefGoogle Scholar
  39. 39.
    Schwartz MA, Lechene C, Ingber DE. Insoluble fibronectin activates the Na+/H+ antiporter by clustering and immobilizing integrin, independent of cell shape. Proc Natl Acad Sci (USA) 1991; 88:7849–7853.CrossRefGoogle Scholar
  40. 40.
    Trevisan R, Yip J, Sarika L, Li LK, Viberti GC. Enhanced collagen synthesis in cultured skin fibroblasts from insulin-dependent diabetic patients with nephropathy. J Am Soc Nephrol 1997 ; 8:1133–1139.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • Roberto Trevisan
    • 1
    • 2
  • Giancarlo Viberti
    • 1
    • 2
  1. 1.Department of Clinical and Experimental MedicineUniversity of PaduaPaduaItaly
  2. 2.Division of MedicineGuy’s and St Thomas’s Medical and Dental SchoolLondonUK

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