Carbon monoxide: An emerging therapy for acute kidney injury

Abstract

Treating acute kidney injury (AKI) represents an important unmet medical need both in terms of the seriousness of this medical problem and the number of patients. There is also a large untapped market opportunity in treating AKI. Over the years, there has been much effort in search of therapeutics with minimal success. However, over the same time period, new understanding of the underlying pathobiology and molecular mechanisms of kidney injury have undoubtedly helped the search for new therapeutics. Along this line, carbon monoxide (CO) has emerged as a promising therapeutic agent because of its demonstrated cytoprotective, and immunomodulatory effects. CO has also been shown to sensitize cancer, but not normal cells, to chemotherapy. This is particularly important in treating cisplatin-induced AKI, a common clinical problem that develops in patients receiving cisplatin therapies for a number of different solid organ malignancies. This review will examine and make the case that CO be developed into a therapeutic agent against AKI.

Keywords: CO-releasing molecules; acute kidney injury; carbon monoxide; nephrotoxicity; organic CO prodrugs.

Figure 1.

Compounds known to induce AKI.

Figure 2.

Formation of cysteine S-cisplatin conjugates. (Summarized based on related reports^– and reviews^,)

Figure 3.

Metabolic activation of AA and formation of DNA adducts.

Figure 4.

The general design and representative compounds of the organic CO prodrugs.

Figure 5.

Other reported organic CO donors.