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Upregulation of Ciliary Neurotrophic Factor (CNTF) and CNTF Receptor ␣ in Rat Kidney with Ischemia-Reperfusion Injury

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Upregulation of Ciliary Neurotrophic Factor (CNTF) and CNTF Receptor ␣ in Rat Kidney with Ischemia-Reperfusion Injury J Am Soc Nephrol 12: 749–757, 2001 Upregulation of Ciliary Neurotrophic Factor (CNTF) and CNTF Receptor ␣ in Rat Kidney with Ischemia-Reperfusion Injury CHUL WOO YANG,* SUN WOO LIM,† KI WHAN HAN,† HEE JONG AHN,* JUNG HEE PARK,* YOUNG HEE KIM,† MATTHIAS KIRSH,‡ JUNG HO CHA,† JOO HYUN PARK,* YONG SOO KIM,* JIN KIM,† and BYUNG KEE BANG* *Division of Nephrology, Department of Internal Medicine, Kangnam St. Mary’s Hospital, and †Department of Anatomy, The College of Medicine, The Catholic University of Korea, Seoul, Korea; and ‡Institute of Anatomy, University of Freiburg, Freiburg, Germany. Abstract. Ciliary neurotrophic factor (CNTF) is presumed to weak and limited to the descending thin limb of the loop of play a role as a survival factor in neuronal cells, but little is Henle. With I/R injury, CNTF mRNA and protein expressions known about its role in the kidney. To investigate this, the were strikingly increased as compared with the sham-operated expression of CNTF and CNTF receptor ␣ (CNTFR ␣) was rat kidney, and the immunoreactivity of CNTF was mainly analyzed in the ischemic rat kidney. An ischemia/reperfusion observed in the regenerating proximal tubules. The expression (I/R) injury was induced by clamping both renal arteries for 45 of CNTFR ␣ mRNA was also increased after I/R injury, and its min. Animals were killed at 1, 2, 3, 5, 7, 14, and 28 d after location and expression patterns were similar to the expression ischemia. The expression of CNTF and CNTFR ␣ was moni- of CNTF. These findings suggest a possible role of CNTF as a tored by reverse transcription-PCR, in situ hybridization, im- growth factor during renal tubular repair processes after I/R munoblotting, immunohistochemistry, and electron micros- injury and an autocrine or paracrine function of CNTF acting copy. In sham-operated rat kidneys, CNTF expression was against CNTFR ␣. The kidney has a remarkable capacity for restoring its structure Ciliary neurotrophic factor (CNTF) was originally identified and function after ischemic injury (1–3). Recovery is depen- as a trophic molecule for the survival of embryonic chicken dent on the ability of the remaining tubular cells to dediffer- ciliary neurons in vitro (9). Subsequent studies have shown that entiate, enter the cell cycle, proliferate, reline the damaged CNTF is a neuronal growth factor that has a regulatory role in areas along the nephron, and then redifferentiate. This replica- local neuronal healing and regeneration (10,11). The CNTF tive repair process of renal tubule cells is mediated predomi- mRNA and protein are widely expressed in the brain, heart, nantly by the paracrine or autocrine release of growth factors, lung, liver, kidney, and testis of the rat, in addition to prefer- and these factors are expressed transiently in a coordinated ential expression in the sciatic nerve (12,13). Apart from neu- manner during renal regeneration (4). ronal tissue, CNTF is most abundant in the kidney, but its role Several growth factors have been identified in the kidney, and precise localization are yet to be determined. and these growth factors act in a coordinated manner. Of these, The effects of CNTF are mediated by a CNTF-specific epidermal growth factor, insulin-like growth factor-1, and he- ligand-binding ␣ subunit (CNTFR ␣) (14,15). Functionally, patocyte growth factor are well known (5). In addition, hepa- CNTF receptors are critical for the developing nervous system rin-binding epidermal growth factor-like growth factor (6), and are needed to sustain life. Whereas disruption of the CNTF fibroblast growth factor (7), and transforming growth factor-␤1 (8) are associated with the repair process. Additional growth gene results in only modest changes within the central nervous ␣ factors are believed to be involved in the repair process after system (16), mice with the CNTFR null mutation (“knock- ischemic injury because of the complicated nature of the outs”) die during the perinatal period and display profound ␣ process. neuron damage (17). The expression of CNTFR mRNA is restricted primarily to nervous system and skeletal muscle, and a small amount of CNTFR ␣ mRNA is present in the kidney Received March 16, 2000. Accepted September 13, 2000. (18) Correspondence to Dr. Jung Ho Cha, Associate Professor, Department of From the data that have accumulated on the role of CNTF as Anatomy, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Ku, a growth factor in nervous tissue, we hypothesized that CNTF 137-701, Seoul, Korea. Phone: 82-2-590-1163; Fax: 82-2-536-3110; E-mail: may play a role as a growth factor in the kidney. To test this, [email protected] the response of CNTF and CNTFR ␣ to ischemia/reperfusion 1046-6673/1204-0749 Journal of the American Society of Nephrology (I/R) injury was evaluated during regeneration of renal tubular Copyright © 2001 by the American Society of Nephrology cells after I/R injury. Our findings support the hypothesis. 750 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 749–757, 2001 Table 1. Oligonucleotide primer pairs for RT-PCR Gene Gene Size Oligonucleotide Primers Position Size Bank CNTF 21 S GAT GGC TTT CGC AGA GCA AAC 77 550 X17457 22 AS GCA CAG TAA AGA AGA GTA GTC T 627 CNTFR␣ 20 S GCT GTG ACC TGG AGG GTA AA 240 425 S54212 20 AS GTG ATA GCC GTG GTG TTG TG 664 GAPDH 20 S AAT GCA TCC TGC ACC ACC AA 469 515 M17701 21 AS GTA GCC ATA TTC ATT GTC ATA 984 Materials and Methods animals (6 sham and 6 I/R injury) were included at each time point. Animal Preparation and Induction of Acute Renal Presence of acute renal failure was determined by measuring the Failure concentration of creatinine in serum at each experimental time point. The serum creatinine levels were measured with an autoanalyzer Male Sprague-Dawley rats, weighing approximately 250 to 300 g, (Roche Diagnostics, Nutley, NJ). The serum creatinine levels (mg/L) were housed under a 12-h light/dark cycle, and food and water were were above 1.0 mg/dl on day 1 after I/R injury. The sham-operated available ad libitum. The experimental protocol used in this study was rats showed no significant difference at each time point, and the approved by the Animal Ethics Review Committees of our Institution. average serum creatinine concentrations were approximately 0.5 Animals were anesthetized with an intraperitoneal injection of ket- mg/L. amine (2 g/kg body wt). After the abdomen was opened through a midline incision, both renal pedicles were exposed and cleaned by blunt dissection. Microvascular clamps were placed on both renal Preservation of Kidneys arteries to block renal blood flow. Core body temperature was main- The kidneys were perfused briefly through the abdominal aorta tained by placing the animals on a homeothermic table. After 45 min, with phosphate-buffered saline (PBS) to rinse out the blood and the clamps were removed and blood flow was returned to the kidneys. subsequently were fixed by in vivo perfusion with a periodate-lysine- Animals were killed at 1, 2, 3, 5, 7, 14, and 28 d after reperfusion. The paraformaldehyde (PLP) solution for 4 min. They were cut into sham operation was performed in a similar manner, except for the sagittal slices and then immersed in PLP overnight at 4°C. After being clamping of the renal vessels. Total number of animals was 84; 12 rinsed in PBS, tissues were dehydrated in a graded series of ethanol Figure 1. Immunoblot (A and B) and immunohistochemical detection (C and D) of proliferating cell nuclear antigen (PCNA) in rat kidney after sham operation and ischemia/reperfusion (I/R) injury. Representative immunoblots for PCNA and relative optical density in cortex (A) and medulla (B). *, P Ͻ 0.05 versus sham. In the sham-operated rat kidney (C), there were few PCNA-positive cells. After ischemia, numerous PCNA-positive cells were observed in the renal tubular cells (D). Optical densities represent the mean Ϯ SEM for six animals. Magnification, ϫ200. J Am Soc Nephrol 12: 749–757, 2001 Upregulation of CNTF and CNTFR ␣ in Ischemic Rat Kidney 751 Figure 3. Immunoblotting for CNTF protein in rat kidneys after sham Figure 2. Semiquantitative reverse transcription-PCR (RT-PCR) for operation and I/R injury. (A) Representative immunoblot for CNTF ciliary neurotrophic factor (CNTF) mRNA using glyceraldehyde-3- protein in the cortex. A band of 22 kD corresponds to the molecular phosphate dehydrogenase (GAPDH). A band of 550 bp corresponds to weight of CNTF protein. (B) Representative immunoblot for CNTF CNTF. Differences in the CNTF/GAPDH ratios indicate the relative protein in the medulla. *, P Ͻ 0.05 versus sham. Optical densities differences in CNTF mRNA levels between the samples. (A) CNTF represent the mean Ϯ SEM for six animals. mRNA expression in the cortex. (B) CNTF mRNA expression in the medulla. *, P Ͻ 0.05 versus sham. Optical densities represent the mean Ϯ SEM for six animals. 0.01. After the sections were washed with 0.05 M Tris buffer, they were dehydrated in a graded series of ethanol and embedded in Epon-812. The embedded 50-␮m-thick sections were examined, and 1 ␮m of semi-thin and embedded in wax (polyethylene glyco 400 disterate; Poly- sections were cut and photographed on Olympus Photomicroscope sciences, Inc., Warrington, PA). For immunohistochemistry using a (Tokyo, Japan) equipped with differential-interference contrast. pre-embedding method, PLP-fixed tissues were cut on a vibratome For the immunoelectron microscopy, some of the immunostained (Lancer Vibratomes Series 10 00; Technical Products International, vibratome sections were postfixed with 1% osmium tetroxide and St. Louis, MO) to a thickness of 50 ␮m.
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