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Better therapeutic drugs are required for treating hypertensive diabetic nephropathy. In our previous study, the Huaju Xiaoji (HJXJ) formula promoted the renal function of patients with diabetes and hypertensive nephropathy. In this study, we investigated the therapeutic effect and regulation mechanism of HJXJ in hypertensive diabetic mice with nephropathy. <jats:italic>Methods<\/jats:italic>. We constructed a mouse hypertensive diabetic nephropathy (HDN) model by treating mice with streptozotocin (STZ) and nomega\u2010nitro\u2010L\u2010arginine methyl ester (LNAME). We also constructed a human glomerular mesangial cell (HGMC) model that was induced by high doses of sugar (30\u2009mmol\/mL) and TGF<jats:italic>\u03b2<\/jats:italic>1 (5\u2009ng\/mL). Pathological changes were evaluated by hematoxylin and eosin (H&amp;E) staining, periodic acid Schiff (PAS) staining, and Masson staining. The fibrosis\u2010related molecules (TGF<jats:italic>\u03b2<\/jats:italic>1, fibronectin, laminin, COL I, COL IV, <jats:italic>\u03b1<\/jats:italic>\u2010SMA, and p\u2010smad2\/3) were detected by enzyme\u2010linked immunosorbent assay (ELISA). The mRNA levels and protein expression of endoplasmic reticulum stress, fibrosis molecules, and their downstream molecules were assessed using qPCR and Western blotting assays. <jats:italic>Results<\/jats:italic>. Administering HJXJ promoted the renal function of HDN mice. HJXJ reduced the expression of ER stress makers (CHOP and GRP78) and lncMGC, miR379, miR494, miR495, miR377, CUGBP2, CPEB4, EDEM3, and ATF3 in HDN mice and model HGMCs. The positive control drugs (dapagliflozin and valsartan) also showed similar effects after treatment with HJXJ. Additionally, in model HGMCs, the overexpression of <jats:italic>CHOP<\/jats:italic> or <jats:italic>lncMGC<\/jats:italic> decreased the effects of HJXJ\u2010M on the level of fibrosis molecules and downstream target molecules. <jats:italic>Conclusion<\/jats:italic>. In this study, we showed that the HJXJ formula may regulate ERS\u2010lncMGC\/miRNA to enhance renal function in hypertensive diabetic mice with nephropathy. This study may act as a reference for further investigating whether combining HJXJ with other drugs can enhance its therapeutic effect. The findings of this study might provide new insights into the clinical treatment of hypertensive diabetic nephropathy with HJXJ.<\/jats:p>","DOI":"10.1155\/2024\/6942156","type":"journal-article","created":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T18:50:08Z","timestamp":1705776608000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Huaju Xiaoji Formula Regulates ERS\u2010lncMGC\/miRNA to Enhance the Renal Function of Hypertensive Diabetic Mice with 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