Evaluation of the expression and function of megalin and cubilin during tubulointerstitial injury induced by early diabetic nephropathy in murine models of type 1 (t1dm) and type 2 (t2dm) diabetes mellitus.

GIRAUD BILLOUD M; EZQUER, FE; BAHAMONDE, J; EZQUER, ME

Mar del Plata - Buenos Aires

Congreso; LX Reunión de la Sociedad Argentina de Investigación Clínica (SAIC). Reunión Anual de la Sociedad Argentina de Fisiología (SAFIS); 2015

Sociedad Argentina de Investigación Clínica

Diabetic nephropathy (DN) is the leading cause of end-stage renaldisease. Changes in albuminuria are considered a hallmark of theonset or progression of DN. A decrease in the expression of tubularalbumin endocytic transporter megalin/cubilin has been associated toDN, but to date there is not a comprehensive study relating earlytubulointerstitial injury (TI) and megalin/cubilin albumin transporters.We evaluated the expression and function of both transporters duringTI induced by early DN murine models of T1DM and T2DM. T1DMinduction: 8-week-old C57BL/6 mice received 200mg/kg ofstreptozotocin, and sacrificed 10 weeks later. T2DM induction: maleC57BKSdb/db were euthanized at 28 weeks of age. We observed asignificant increase of interstitial collagen deposits (T1DM vs normal),accompanied by an increase of α-SMA (T1DM vs normal) and Col IVtissue expression (T1DM/T2DM vs normal). T1DM animals showed asignificant decrease in body weight during the experiments, whileT2DM was increased. Kidney size of T1DM/T2DM was alsosignificantly increased. Albumin and VDBP urinary excretion (ELISA)were significantly increased in both diabetic models. Also, we observedin T1DM a significant decrease in surface expression (IFI), mRNAexpression and total amount of protein (WB) of megalin. Only asignificant decrease in total cubilin (WB) was observed in T1DM. InT2DM we found only a significant decrease in total megalin (WB). Ourresults demonstrate that albumin and VDBP urinary excretion areprobably associated to a diminished expression of megalin and cubilinin T1DM. In T2DM the malfunction of both transporters apparently arenot only associated to a decrease in their expression, therefore otherpossible mechanisms need to be explored. Future efforts should bedirected to enlighten the intracellular mechanisms of endocytictranscytocis of megalin/cubilin receptors and the possible proteinshedding from the epithelial surface in DN.