Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats
Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation...
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MDPI AG
2021-11-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/11/3044 |
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| author | Szu-Yu Liu Chia-Chang Huang Shiang-Fen Huang Tsai-Ling Liao Nai-Rong Kuo Ying-Ying Yang Tzu-Hao Li Chih-Wei Liu Ming-Chih Hou Han-Chieh Lin |
| author_facet | Szu-Yu Liu Chia-Chang Huang Shiang-Fen Huang Tsai-Ling Liao Nai-Rong Kuo Ying-Ying Yang Tzu-Hao Li Chih-Wei Liu Ming-Chih Hou Han-Chieh Lin |
| author_sort | Szu-Yu Liu |
| collection | DOAJ |
| description | Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats. |
| first_indexed | 2024-03-10T05:36:01Z |
| format | Article |
| id | doaj.art-103438a3d81240c499a61e067294950a |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:36:01Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-103438a3d81240c499a61e067294950a2023-11-22T22:50:31ZengMDPI AGCells2073-44092021-11-011011304410.3390/cells10113044Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic RatsSzu-Yu Liu0Chia-Chang Huang1Shiang-Fen Huang2Tsai-Ling Liao3Nai-Rong Kuo4Ying-Ying Yang5Tzu-Hao Li6Chih-Wei Liu7Ming-Chih Hou8Han-Chieh Lin9Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, TaiwanDepartment of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei 11217, TaiwanFaculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, TaiwanDepartment of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, TaiwanDepartment of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, TaiwanFaculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, TaiwanFaculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei 11217, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei 11217, TaiwanEndotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.https://www.mdpi.com/2073-4409/10/11/3044endotoxemialipopolysaccharidepioglitazonecirrhosisPPARγTNFα |
| spellingShingle | Szu-Yu Liu Chia-Chang Huang Shiang-Fen Huang Tsai-Ling Liao Nai-Rong Kuo Ying-Ying Yang Tzu-Hao Li Chih-Wei Liu Ming-Chih Hou Han-Chieh Lin Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats Cells endotoxemia lipopolysaccharide pioglitazone cirrhosis PPARγ TNFα |
| title | Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats |
| title_full | Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats |
| title_fullStr | Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats |
| title_full_unstemmed | Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats |
| title_short | Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats |
| title_sort | pioglitazone ameliorates acute endotoxemia induced acute on chronic renal dysfunction in cirrhotic ascitic rats |
| topic | endotoxemia lipopolysaccharide pioglitazone cirrhosis PPARγ TNFα |
| url | https://www.mdpi.com/2073-4409/10/11/3044 |
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