Impact of autophagy on the development of senescence in protocol biopsies in kidney transplant patients

GIORDANI, M. C.; VECINO, C.; CRISTIANSSEN, S. B.; ALEJANDRO JAVIER ROPOLO; VILLAMIL CORTEZ, S. K.; IMPERIALI, N.; GROPPA, S. R.; VACCARO, M. I.

Simposio; WIA Annual Symposium 2022; 2022

Women in Autophagy

In kidney transplant, the 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. VMP1 vacuole membrane protein1 is a transmembrane protein involved in the autophagy process. Patients with chronic allograft dysfunction have downregulation of autophagy. 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 inmunofluorescence of VMP1 was performed on paraffin 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. Eighteen protocol biopsies from 6 cadaveric kidney Tx patients were analyzed. All patients had triple immunosuppressive regimen. In VMP1 positive samples, it was found as granular intracytoplasmic vacuole in proximal and distal tubule cells, in arterial smooth muscle cells. Nuclear p16INK4a staining was positive in proximal tubules and glomerular endothelial cells. Semiquantitative analysis of the expression of both markers is represented in Table 1. A progressive increase in the expression of the autophagy marker VMP1, from the pre-implant biopsy to one year after transplantation, was seen in samples from patients (1, 3, 5 ) who had no expression of the senescence marker p16 INK4a. Opposite to this, patients 2, 4 and 6 expressed p16 INK4 at one year post transplant and had no expression of VMP1. We conclude that in renal biopsies from 6 kidney Tx patients, those who expressed the cell-protective autophagy marker VMP1 did not express the senescence marker p16 INK4a. A better understanding of this phenomena could allow the development of therapies to increase graft longevity.