PMID- 37561129 OWN - NLM STAT- MEDLINE DCOM- 20230914 LR - 20231031 IS - 1432-2013 (Electronic) IS - 0031-6768 (Print) IS - 0031-6768 (Linking) VI - 475 IP - 10 DP - 2023 Oct TI - Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis. PG - 1161-1176 LID - 10.1007/s00424-023-02844-6 [doi] AB - Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-kappaB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (H(2)O(2)), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium. CI - (c) 2023. The Author(s). FAU - Rizk, Fatma H AU - Rizk FH AUID- ORCID: 0000-0002-4945-4017 AD - Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt. Fatma.rizk@med.tanta.edu.eg. FAU - El Saadany, Amira A AU - El Saadany AA AUID- ORCID: 0000-0002-9598-5361 AD - Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Atef, Marwa Mohamed AU - Atef MM AUID- ORCID: 0000-0002-5942-4719 AD - Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Abd-Ellatif, Rania Nagi AU - Abd-Ellatif RN AUID- ORCID: 0000-0002-4235-5884 AD - Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - El-Guindy, Dina M AU - El-Guindy DM AUID- ORCID: 0000-0003-3419-0618 AD - Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Abdel Ghafar, Muhammad T AU - Abdel Ghafar MT AUID- ORCID: 0000-0002-0621-4291 AD - Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Shalaby, Marwa M AU - Shalaby MM AUID- ORCID: 0000-0001-6655-5314 AD - Department of Medical Microbiology and Immunology, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Hafez, Yasser Mostafa AU - Hafez YM AUID- ORCID: 0000-0003-0306-2357 AD - Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Mashal, Shaimaa Samir Amin AU - Mashal SSA AUID- ORCID: 0000-0002-7869-7712 AD - Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Basha, Eman H AU - Basha EH AUID- ORCID: 0000-0002-8184-6459 AD - Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Faheem, Heba AU - Faheem H AUID- ORCID: 0000-0003-0868-4737 AD - Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Barhoma, Ramez Abd-Elmoneim AU - Barhoma RA AUID- ORCID: 0000-0001-5750-1429 AD - Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230810 PL - Germany TA - Pflugers Arch JT - Pflugers Archiv : European journal of physiology JID - 0154720 RN - OR3S9IF86U (urinastatin) RN - 5W494URQ81 (Streptozocin) RN - AYI8EX34EU (Creatinine) RN - BBX060AN9V (Hydrogen Peroxide) SB - IM MH - Rats MH - Animals MH - Male MH - *Diabetic Nephropathies/drug therapy MH - Streptozocin/metabolism/pharmacology/therapeutic use MH - Creatinine/metabolism/pharmacology MH - Hydrogen Peroxide/pharmacology MH - *Diabetes Mellitus, Experimental/metabolism MH - Rats, Wistar MH - Kidney/metabolism PMC - PMC10499971 OTO - NOTNLM OT - Diabetic nephropathy OT - Gut-kidney axis OT - Mitochondrial homeostasis OT - Ulinastatin COIS- The authors declare no competing interests. The authors declare that they have no conflicts of interest. EDAT- 2023/08/10 12:42 MHDA- 2023/09/14 06:42 PMCR- 2023/08/10 CRDT- 2023/08/10 11:04 PHST- 2023/05/19 00:00 [received] PHST- 2023/07/21 00:00 [accepted] PHST- 2023/07/17 00:00 [revised] PHST- 2023/09/14 06:42 [medline] PHST- 2023/08/10 12:42 [pubmed] PHST- 2023/08/10 11:04 [entrez] PHST- 2023/08/10 00:00 [pmc-release] AID - 10.1007/s00424-023-02844-6 [pii] AID - 2844 [pii] AID - 10.1007/s00424-023-02844-6 [doi] PST - ppublish SO - Pflugers Arch. 2023 Oct;475(10):1161-1176. doi: 10.1007/s00424-023-02844-6. Epub 2023 Aug 10.