Induction of p16Ink4a Gene Expression in Heme Protein-Induced AKI and by Heme: Pathophysiologic Implications

Understanding the pathogenetic basis for AKI involves the study of ischemic and nephrotoxic models of AKI, the latter including heme protein–mediated AKI (HP-AKI). Recently, interest has grown regarding the role of senescence as a mechanism of kidney injury, including AKI. We examined whether senescence occurs in HP-AKI and potential inducers of and the role of a key driver of senescence, namely, p16Ink4a, in HP-AKI.

The pathogenesis of HP-AKI involves senescence and the induction of p16Ink4a, the latter driven, in part, by hemoglobin, myoglobin, and heme.

The long-established murine glycerol model of HP-AKI was used, and indices of senescence were examined. To evaluate the interaction of heme and p16Ink4a expression, murine models of genetic deficiency of hemopexin (HPX) and heme oxygenase-1 (HO-1) were used. To determine the involvement of p16Ink4a in HP-AKI, the population of p16Ink4a-expressing cells was reduced using the INK-ATTAC model.

Using multiple indices, a senescence phenotype appears in the kidney within hours after the induction of HP-AKI. This phenotype includes significant upregulation of p16Ink4a. p16Ink4a is upregulated in the kidney after the individual administration of myoglobin, hemoglobin, and heme, as well as in renal epithelial cells exposed to heme in vitro. Genetic deficiencies of HPX and HO-1, which, independently, are expected to increase heme content in the kidney, exaggerate induction of p16Ink4a in the kidney and exacerbate HP-AKI, the latter shown in the present studies involving HPX−/− mice and in previous studies involving HO-1−/− mice. Finally, reduction in the population of p16Ink4a-expressing cells in the kidney improves renal function in HP-AKI even within 24 hours. Conclusions: The pathogenesis of HP-AKI involves senescence and the induction of p16Ink4a, the latter driven, in part, by hemoglobin, myoglobin, and heme.