Back
In kidney transplant, tissue expression of cyclin-dependent kinase inhibitors p16INK4a, a cellular senescence marker, is a strong predictor of poor allograft outcome. Autophagy is a tightly regulated cellular self-degradation recycling process. Vacuole membrane protein1 (VMP1) is a transmembrane protein involved in the initial steps of the autophagy process. Both senescence and autophagy are activated in response to kidney injury during transplantation. A relationship between both seems to exist, although it is still poorly understood, and human studies are scarce. We aim to assess the relationship between senescence and autophagy through tissue expression of p16INK4a and VMP1 in renal transplants patients.
Protocol transplant (Tx) kidney biopsies at zero hour, 1 and 12 post Tx months in patients who consent were included. Immunohistochemistry staining for p16 INK4a and immunofluorescence of VMP1 was performed on paraffin and fresh biopsy sections. We evaluated the extent of nuclear p16INK4a staining and VMP1 positive expression as a punctate cytoplasmic structure in the renal cortex. Semiquantitative scoring of p16INK4a and VMP1 staining intensity (1-3; 3 representing maximum intensity) was analyzed. Thirty-three biopsies’ samples from 11 cadaveric kidney Tx patients were analyzed. All patients had triple immunosuppressive regimen.
VMP1 positive samples expressed the marker as granular intracytoplasmic vacuoles in proximal and distal tubule cells and in arterial smooth muscle cells. Nuclear p16INK4a staining was positive in proximal tubules and glomerular endothelial cells. We observed two distinctive patterns of tissue expression of both markers: Pattern A (patients 1, 3, 6, 7, 11): showed a progressive increase in expression of the autophagy marker VMP1, from the pre-implant biopsy to one year after transplantation, with no expression of p16 INK4a. Opposite to this, Pattern B samples ( patients 2, 4, 5, 8, 9, 10) showed expressed p16 INK4 at one year post transplant and had No expression of VMP1. In this allograft biopsies from eleven kidney Tx patients, those who expressed the cell-protective autophagy marker VMP1 did not express the senescence marker p16 INK4a one year after transplant. In the six patients who expressed the senescence marker one year after transplant, autophagy disappeared.
It seems that the presence of the autophagy marker VMP1 is inversely correlated with senescence. A better understanding of this phenomena could allow the development of therapies to increase graft longevity