*Purpose: Interstitial Fibrosis and Tubular Atrophy (IFTA) is the most common cause of long-term graft failure following renal transplant. There is currently no effective therapy. One of the hallmarks of IFTA is the development of interstitial fibrosis and loss of normal renal architecture. Autophagy is a conserved cellular process that is activated secondary to cellular stress following ischemia-reperfusion injury resulting in the degradation of cytoplasmic components. Previous studies have shown that promotion of autophagy via Beclin-1 factor reduced fibrosis and attenuated production of cytokines. Therefore, enhancing autophagy may become an effective approach to control fibrosis. In this study, we will utilize an established mouse model of Unilateral Ureteral Obstruction (UUO) to test whether a dynamic change of autophagy in kidney following injury, correlates with renal fibrosis.

*Methods: Mice underwent UUO as previously described. Tissue samples were prepared 1-, 2-, and 4-weeks post injury. Tissue samples were probed with markers of integrated stress response (ISR; ATF, elF2S1, and pERK) as well as makers of inflammation (phosphorylated STING). Additionally, autophagy initiation marker, LC3-II, and degradation marker, p62 were used. Samples were examined histologically and compared to uninjured kidneys from the same animal for strength of expression of these markers and then correlated with trichrome straining and collagen expression for fibrosis.

*Results: There was a stepwise increase in expression of collagen as well as trichrome staining 2- and 4-weeks post-injury. Additionally, markers of ISR; ATF, elF2S1 and pERK were increased 3-fold in the renal cortex and medulla with a decreased but increased expression in the peri-glomerular spaces. STING protein phosphorylation at ser 366 increased 3-fold throughout the kidney 4-weeks post injury. Autophagy initiation factor, LC3II, and autophagy degradation marker, p62, were likewise increased 3-fold in the cortex of injured kidneys 4 weeks post-injury

*Conclusions: In the setting of renal fibrosis following UUO, ISR phosphorylation signals indicate increasing enzyme activation, and Sting phosphorylation indicates activation of Sting-dependent inflammation post-injury. This is only seen in 4-week UUO kidneys, suggesting a later inflammatory process associated with increasing fibrosis. Increases in autophagy marker expression indicate that the autophagy flux is not able to be completed due to a blockage at the lysosomal degradation step. Thus, UUO causes an insufficient, maladaptive autophagy. Further work will delineate the role of autophagy in post-injury fibrosis and lead to potential therapeutic interventions aimed at ameliorating IFTA.

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