Low Ca2+ pump activity in diabetic nephropathy

Elevated cell Na+-H+ exchange (NHE) activity characterizes diabetic nephrop athy (DN), but the mechanisms of this abnormality are unclear. Recent evide nce suggests that NHE and the Ca2+ pump share similar regulatory pathways, but whether abnormalities in Ca2+ metabolism characterize DN is not known. We investigated Ca2+ efflux rates, NHE activity, cytosolic Ca2+ ([Ca2+](i)) concentrations, and intracellular pH (pH(i)) in human skin fibroblasts fro m 20 patients with type 1 (insulin-dependent) diabetes and nephropathy; 20 patients with diabetes with normoalbuminuria matched for age, sex, and dura tion of diabetes; and 10 individuals without diabetes. Ca2+ pump-mediated C a2+ efflux was significantly lower in patients with nephropathy than in pat ients with normoalbuminuria and individuals without diabetes (0.074 +/- 0.0 1 versus 0.115 +/- 0.01 versus 0.131 +/- 0.02 nmol.mg(protein)(-1).min(-1); analysis of variance [ANOVA], P = 0.015). Elevated maximal velocity of the Na+-H+ exchanger was confirmed in fibroblasts from patients with nephropat hy (14.4 +/- 1.2 versus 7.1 +/- 0.7 versus 8.0 +/- 1.2 mmol H+.l cell(-1).m in(-1); ANOVA, P < 0.0001). A reverse correlation between Ca2+ pump activit y and NHE rates could be shown. Adjustment for glycated hemoglobin and plas ma lipid levels did not affect these findings. Finally, [Ca2+](i) concentra tions and pH(i) were normal in all patients. Low Ca2+ pump activity is a co ncomitant event of elevated NHE rates in DN; the molecular dysfunction(s) u nderlying these abnormalities remains to be established. (C) 2001 by the Na tional Kidney Foundation, Inc.