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The current study explored the renoprotective impact of montelukast (Mon) against streptozotocin (STZ)-induced DN in rats compared to a standard anti-hyperglycemic insulin (Ins) treatment. Diabetes was induced by a single dose of STZ (55\u00a0mg\/kg). Diabetic rats were treated with Mon (10 and 20\u00a0mg\/kg, oral gavage) for eight weeks. Mon administration for 8\u00a0weeks after induction of diabetes conferred significant dose-dependent renoprotection, independent of blood glucose levels (unlike Ins), as evidenced by the improvement in serum creatinine, and blood urea nitrogen (BUN), and ameliorated STZ-induced renal necrotic, inflammatory alterations, and renal fibrosis. Additionally, Mon treatment in diabetic rats significantly restored redox hemostasis as evidenced by malondialdehyde (MDA) and total antioxidant capacity (TAC) levels; significantly reduced the renal expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-\u03baB) (in the nucleus), NOD-like receptor family pyrin domain containing (NLRP) 3, and interleukin (IL)-1\u03b2. Moreover, Mon administration ameliorated the dysregulation in autophagy as evidenced by p62 and microtubule-associated protein 1A\/1B-light chain 3 (LC3)-II levels. In conclusion, the renoprotective effect of Mon is potentially associated with its modulatory effect on inflammatory cytokines, antioxidant properties, and autophagy.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>Renoprotective effect of montelukast and its underlying pathway: Hyperglycemia and advanced glycation end products (AGEs) stimulate the release of high mobility group box (HMGB) 1 from necrotic and inflammatory cells. HMGB1 is considered as one of the endogenous ligands of toll-like receptor (TLR) 4, and the interaction of HMGB1 with TLR4 results in a subsequent translocation of nuclear factor kappa B (NF-\u03baB) from the cytoplasm into the nucleus inducing an inflammatory response. NF-\u03baB is a key mediator of the priming signal responsible for the activation of NOD-like receptor family pyrin domain containing (NLRP) 3 inflammasome by stimulating the expression of both NLRP3 and pro- interleukin (IL)-1\u03b2, which is then converted to IL-1\u03b2 by to mediate inflammation. NLRP3 can induce reactive oxygen species production, while autophagy inhibits AGEs and NLRP3 accumulation. Montelukast show an inhibitory effect on HMGB1, TLR4, NF-\u03baB, NLRP3, and IL-1\u03b2 and has autophagy stimulating characteristics indicating its potential renoprotective effect.<\/jats:p>","DOI":"10.1007\/s10787-023-01301-1","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T02:01:57Z","timestamp":1690423317000},"page":"495-508","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Ameliorative effect of montelukast against STZ induced diabetic nephropathy: targeting HMGB1, TLR4, NF-\u03baB, NLRP3 inflammasome, and autophagy pathways"],"prefix":"10.1007","volume":"32","author":[{"given":"Ahmed M.","family":"Awad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally L.","family":"Elshaer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajashekhar","family":"Gangaraju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6651-6187","authenticated-orcid":false,"given":"Rania R.","family":"Abdelaziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manar A.","family":"Nader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"1301_CR1","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1681\/ASN.2006040377","volume":"17","author":"M Abbate","year":"2006","unstructured":"Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? 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