PMID- 26450610 OWN - NLM STAT- MEDLINE DCOM- 20160726 LR - 20220316 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 13 DP - 2015 Oct 8 TI - Cofilin1 is involved in hypertension-induced renal damage via the regulation of NF-kappaB in renal tubular epithelial cells. PG - 323 LID - 10.1186/s12967-015-0685-8 [doi] LID - 323 AB - BACKGROUND: Inflammation mediated by nuclear factor-kappaB (NF-kappaB) plays a critical role in the pathogenesis of hypertensive nephropathy (HN). Cytoskeletal remodelling is necessary for the activation of NF-kappaB. An actin-binding protein, cofilin-1 promotes dynamic alterations to the cytoskeleton by severing actin filaments. However, whether cofilin1 modulates NF-kappaB activity via cytoskeletal remodelling in the setting of hypertensive renal damage and what mechanisms underlie this phenomenon, remain unknown. METHODS: Twenty-one-week old spontaneously hypertensive rats (SHRs) were treated with an antioxidant (100 or 250 mg kg(-1) day(-1)), grape seed proanthocyanidins extract (GSPE), for 22 weeks. Twenty-four-hour urinary protein, serum creatinine and urea nitrogen levels were measured. Haematoxylin and eosin (HE) staining was performed, and the expression levels of renal cortex cofilin1, monocyte chemotactic protein 1 (MCP1), interleukin-1beta (IL1beta) and NF-kappaB were evaluated via either Western blotting or immunohistochemistry. In vitro, human proximal renal tubular epithelial cells (HK-2 cells) were pre-incubated either with or without GSPE and subsequently treated with angiotensinII (AngII). Furthermore, a lentiviral shRNA-vector was utilized to knockdown cofilin1 expression in the HK-2 cells, which were stimulated with AngII. Actin filaments, NF-kappaB activity and several downstream inflammatory factors, including MCP1 and IL-1beta, were investigated. RESULTS: In addition to elevated blood pressure and 24 h urinary protein levels, NF-kappaB activity and the expression levels of MCP1 and IL-1beta were significantly increased, resulting in tubulointerstitial inflammatory infiltration in SHRs. The phosphorylation (inactivation) of cofilin1 was increased in the kidneys of the SHRs. In vitro, AngII stimulation resulted in the phosphorylation of cofilin1, the formation of actin stress fibres and nuclear translocation of NF-kappaB p65 in the HK2 cells. Both GSPE pretreatment and the shRNA knockdown of cofilin1 inhibited Rel/p65 nuclear translocation, as well as the expression of both MCP-1 and IL-1beta in the AngII-induced HK2 cells. CONCLUSION: These results demonstrate that cofilin1 is involved in hypertensive nephropathy by modulating the nuclear translocation of NF-kappaB and the expression of its downstream inflammatory factors in renal tubular epithelial cells. FAU - Wang, Quan-Zhen AU - Wang QZ AD - Department of Geriatric Cardiology, Qilu Hospital of Shandong University, 107 Wenhua Xi Rd, 250012, Jinan, People's Republic of China. wangquanzhen1986@163.com. FAU - Gao, Hai-Qing AU - Gao HQ AD - Department of Geriatric Cardiology, Qilu Hospital of Shandong University, 107 Wenhua Xi Rd, 250012, Jinan, People's Republic of China. gaohaiqing@sdu.edu.cn. FAU - Liang, Ying AU - Liang Y AD - Department of Geriatric Cardiology, Qianfuoshan Hospital of Shandong Province, 16766 Jingshi Rd, 250000, Jinan, People's Republic of China. liangying2970@sina.com. FAU - Zhang, Jun AU - Zhang J AD - Department of Geriatric Cardiology, Qilu Hospital of Shandong University, 107 Wenhua Xi Rd, 250012, Jinan, People's Republic of China. junermiaomiao@163.com. FAU - Wang, Jian AU - Wang J AD - Department of Geriatric Cardiology, Qilu Hospital of Shandong University, 107 Wenhua Xi Rd, 250012, Jinan, People's Republic of China. jian19880907@126.com. FAU - Qiu, Jie AU - Qiu J AD - Department of Geriatric Cardiology, Qilu Hospital of Shandong University, 107 Wenhua Xi Rd, 250012, Jinan, People's Republic of China. drqiujie@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151008 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (Antioxidants) RN - 0 (CFL1 protein, human) RN - 0 (Cfl1 protein, rat) RN - 0 (Chemokine CCL2) RN - 0 (Cofilin 1) RN - 0 (Grape Seed Extract) RN - 0 (Grape Seed Proanthocyanidins) RN - 0 (IL1B protein, rat) RN - 0 (Interleukin-1beta) RN - 0 (NF-kappa B p50 Subunit) RN - 0 (NFKB1 protein, human) RN - 0 (Proanthocyanidins) RN - 0 (RNA, Small Interfering) RN - 11128-99-7 (Angiotensin II) RN - 8W8T17847W (Urea) RN - AYI8EX34EU (Creatinine) RN - N762921K75 (Nitrogen) SB - IM MH - Angiotensin II/metabolism MH - Animals MH - Antioxidants/chemistry MH - Chemokine CCL2/metabolism MH - Cofilin 1/*metabolism MH - Creatinine/blood MH - Cytoskeleton/metabolism MH - Epithelial Cells/*metabolism MH - Gene Expression Regulation MH - Grape Seed Extract/chemistry MH - Humans MH - Hypertension/*physiopathology MH - Inflammation MH - Interleukin-1beta/metabolism MH - Kidney Tubules/*metabolism MH - Male MH - NF-kappa B p50 Subunit/*metabolism MH - Nitrogen/analysis MH - Proanthocyanidins/chemistry MH - RNA, Small Interfering/metabolism MH - Rats MH - Rats, Inbred SHR MH - Renal Insufficiency/*metabolism MH - Urea/analysis PMC - PMC4599745 EDAT- 2015/10/10 06:00 MHDA- 2016/07/28 06:00 PMCR- 2015/10/08 CRDT- 2015/10/10 06:00 PHST- 2015/03/29 00:00 [received] PHST- 2015/10/02 00:00 [accepted] PHST- 2015/10/10 06:00 [entrez] PHST- 2015/10/10 06:00 [pubmed] PHST- 2016/07/28 06:00 [medline] PHST- 2015/10/08 00:00 [pmc-release] AID - 10.1186/s12967-015-0685-8 [pii] AID - 685 [pii] AID - 10.1186/s12967-015-0685-8 [doi] PST - epublish SO - J Transl Med. 2015 Oct 8;13:323. doi: 10.1186/s12967-015-0685-8.