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Hb facilitates oxygen (O<jats:sub>2<\/jats:sub>) delivery but poses challenges outside red blood cells (RBCs) due to toxic Hb and heme mechanisms. These are managed by binding to serum proteins like Haptoglobin (Hp) and Hemopexin (Hpx). During hemolysis, depletion of Hp and Hpx leaves tissues vulnerable to Hb and heme. To address this, we developed the ApoHb\u2010Hp complex, based on Apohemoglobin, which is produced by removing heme from Hb, conjugated with Hp. This complex acts as a dual scavenger for Hb and heme, preventing tissue damage. Our findings demonstrate that ApoHb\u2010Hp significantly protects MPC5 podocytes from Hb\u2010induced damage. Fluorescent staining showed a higher percentage of nephrin\u2010positive cells in the ApoHb\u2010Hp group, and MTT assays revealed enhanced cell viability compared to Hb alone. Additionally, ApoHb\u2010Hp reduced reactive oxygen species (ROS) production, with the Hb group exhibiting significantly elevated ROS levels. The ApoHb\u2010Hp complex mitigated the depletion of protective mechanisms, as shown by significant increases in superoxide dismutase (SOD) and glutathione (GSH). Moreover, ApoHb\u2010Hp treatment reduced the activation of the NLRP3 inflammasome signaling pathway and inflammatory cytokines IL\u20101\u03b2 and IL\u201018. These findings underscore the therapeutic potential of ApoHb\u2010Hp in mitigating Hb\u2010induced renal damage by preserving podocyte viability and reducing oxidative stress. Overall, ApoHb\u2010Hp maintained protective mechanisms depleted otherwise by Hb. These findings highlight ApoHb\u2010Hp's potential as a therapeutic agent against Hb\u2010induced renal damage, offering insights into its mechanisms and implications for treating conditions involving hemolysis.<\/jats:p>","DOI":"10.14814\/phy2.70132","type":"journal-article","created":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T04:39:14Z","timestamp":1732336754000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mitigating hemoglobin\u2010induced nephropathy: <scp>ApoHb<\/scp>\u2010hp protection of podocytes"],"prefix":"10.14814","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0101-4628","authenticated-orcid":false,"given":"Daniela","family":"Lucas","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of California San Diego  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4832-3661","authenticated-orcid":false,"given":"Carlos","family":"Munoz","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of California San Diego  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1499-9620","authenticated-orcid":false,"given":"Quintin","family":"O'Boyle","sequence":"additional","affiliation":[{"name":"William G. 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