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

Key Points: In heme protein–mediated AKI (HP-AKI), a senescence phenotype promptly occurs, and increased expression of p16 contributes to HP-AKI. Renal p16 expression is induced by hemoglobin, myoglobin, and heme and in renal epithelial cells exposed to heme . Impairing the binding or degradation of heme by hemopexin deficiency or heme oxygenase-1 deficiency, respectively, further upregulates p16.

Background: 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, p16, in HP-AKI.

Methods: The long-established murine glycerol model of HP-AKI was used, and indices of senescence were examined. To evaluate the interaction of heme and p16 expression, murine models of genetic deficiency of hemopexin () and heme oxygenase-1 () were used. To determine the involvement of p16 in HP-AKI, the population of p16-expressing cells was reduced using the model.

Results: Using multiple indices, a senescence phenotype appears in the kidney within hours after the induction of HP-AKI. This phenotype includes significant upregulation of p16. p16 is upregulated in the kidney after the individual administration of myoglobin, hemoglobin, and heme, as well as in renal epithelial cells exposed to heme . Genetic deficiencies of and , which, independently, are expected to increase heme content in the kidney, exaggerate induction of p16 in the kidney and exacerbate HP-AKI, the latter shown in the present studies involving mice and in previous studies involving mice. Finally, reduction in the population of p16-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 p16, the latter driven, in part, by hemoglobin, myoglobin, and heme.