title: Upregulation of HNF-1β during experimental acute kidney injury plays a crucial role in renal tubule regeneration.
abstract: Hepatocyte nuclear factor-1β (HNF-1β) is a transcription factor expressed in the kidney, liver, pancreas, and other organs. Mutations of HNF-1β cause maturity-onset diabetes of the young type 5 (MODY5). The aims of this study were to investigate the functional roles of the HNF-1β/suppressor of cytokine signaling-3 (SOCS-3) pathway in tubule damage after acute kidney injury (AKI) both in vivo and in vitro and to examine the effect of HNF-1β on renal tubule formation. To clarify the significance of the HNF-1β/SOCS-3 pathway in AKI, we used a rat ischemia/reperfusion (I/R) AKI model and cultured renal tubular cells (NRK-52E cells). Western blot analysis showed that HNF-1β and polycystic kidney disease 2 (PKD2) expressions were increased at 3-12 h and 12-24 h after I/R, respectively. The expression level of SOCS-3 was decreased at 3-48 h. Immunohistological examination revealed that expression of HNF-1β was increased in proximal tubules. Overexpression of HNF-1β resulted in decreased SOCS-3 expression, activation of signal transducer and activator of transcription 3 (STAT3) and Erk, and increased [(3)H]thymidine uptake in the presence of hepatocyte growth factor. Furthermore, tubule formation in three-dimensional gels was inhibited by dominant-negative HNF-1β. Our study shows that HNF-1β is upregulated after AKI in proximal tubular cells and that HNF-1β controls cellular proliferation and tubule formation by regulating SOCS-3 expression and STAT3/Erk activation. Therefore, the current study unravels the physiological and pathological significance of the HNF-1β pathway in AKI.
authors: Dept. of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Japan.
authors: Koji
authors: K
authors: Ogata
authors: Yoshiko
authors: Y
authors: Shimamura
authors: Kazu
authors: K
authors: Hamada
authors: Masayuki
authors: M
authors: Hisa
authors: Masayuki
authors: M
authors: Bun
authors: Nazuki
authors: N
authors: Okada
authors: Kosuke
authors: K
authors: Inoue
authors: Yoshinori
authors: Y
authors: Taniguchi
authors: Masayuki
authors: M
authors: Ishihara
authors: Toru
authors: T
authors: Kagawa
authors: Taro
authors: T
authors: Horino
authors: Shimpei
authors: S
authors: Fujimoto
authors: Yoshio
authors: Y
authors: Terada
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology*; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000096:biosynthesis / Q000235:genetics*; D007684:Kidney Tubules / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D015427:Reperfusion Injury / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000502:physiology*; D050396:TRPP Cation Channels / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D051539:Hepatocyte Nuclear Factor 1-beta; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050396:TRPP Cation Channels; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat