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Two of the most common causes of KD are diabetes and acute kidney injury (AKI), both of which induce mitochondrial dysfunction resulting in renal proximal tubular damage\/necrosis. Thus, pharmacological induction of mitochondrial biogenesis (MB) may provide a therapeutic strategy to block the onset\/progression of KD. Here, we evaluated the pharmacological and potential therapeutic effects of a novel MB\u2010inducing oxindole agent, <jats:bold>MC16<\/jats:bold>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Primary cultures of rabbit renal proximal tubule cells (RPTCs) were used to evaluate the cellular signalling and MB\u2010inducing effects of <jats:bold>MC16<\/jats:bold>. Mice were used to determine the MB\u2010inducing effects of <jats:bold>MC16<\/jats:bold> in vivo, and the metabolic effects of <jats:bold>MC16<\/jats:bold> on the renal cortical metabolome. Mouse models of AKI and diabetic kidney disease (DKD) were used to demonstrate the therapeutic potential of <jats:bold>MC16<\/jats:bold> to ameliorate acute and diabetic nephropathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p><jats:bold>MC16<\/jats:bold> activated the PI3K\u2010AKT\u2010eNOS\u2010FOXO1 axis and induced MB in RPTCs. <jats:bold>MC16<\/jats:bold> induced MB and altered the renal cortical metabolome of mice. <jats:bold>MC16<\/jats:bold> accelerated renal recovery, reduced vascular permeability, and diminished mitochondrial dysfunction following AKI. <jats:bold>MC16<\/jats:bold> decreased diabetes\u2010induced renal swelling, improved renal and mitochondrial function, and diminished interstitial fibrosis in DKD mouse models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p><jats:bold>MC16<\/jats:bold> is a novel compound that induces MB and ameliorates acute and diabetic nephropathy in mice. This study underscores that targeting MB following the onset of renal\/metabolic insults may provide a therapeutic strategy to mitigate the onset and\/or progression of KD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17440","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T08:44:52Z","timestamp":1738313092000},"page":"1912-1929","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MC16 promotes mitochondrial biogenesis and ameliorates acute and diabetic nephropathy"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4643-3229","authenticated-orcid":false,"given":"Austin D.","family":"Thompson","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Arizona  Tucson Arizona USA"},{"name":"U.S. Department of Veterans Affairs Southern Arizona VA Health Care System  Tucson Arizona USA"},{"name":"Southwest Environmental Health Science Center University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8237-414X","authenticated-orcid":false,"given":"Kevin A.","family":"Hurtado","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Arizona  Tucson Arizona USA"},{"name":"Southwest Environmental Health Science Center University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Janda","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1234-5482","authenticated-orcid":false,"given":"Natalie E.","family":"Scholpa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Arizona  Tucson Arizona USA"},{"name":"U.S. Department of Veterans Affairs Southern Arizona VA Health Care System  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baerbel","family":"Rohrer","sequence":"additional","affiliation":[{"name":"MitoChem Therapeutics, Inc.  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