• Clinical and Experimental Pediatrics
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• v.53 no.7
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• pp.735-740
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• 2010

Renal fibrosis, characterized by tubulointerstitial fibrosis and glomerulosclerosis, is the final manifestation of chronic kidney disease. Renal fibrosis is characterized by an excessive accumulation and deposition of extracellular matrix components. This pathologic result usually originates from both underlying complicated cellular activities such as epithelial-to-mesenchymal transition, fibroblast activation, monocyte/macrophage infiltration, and cellular apoptosis and the activation of signaling molecules such as transforming growth factor beta and angiotensin II. However, because the pathogenesis of renal fibrosis is extremely complicated and our knowledge regarding this condition is still limited, further studies are needed.

• BMB Reports
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• v.56 no.3
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• pp.196-201
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• 2023

Renal fibrosis is the final manifestation of chronic kidney disease (CKD) regardless of etiology. Hypoxia-inducible factor-2 alpha (HIF-2α) is an important regulator of chronic hypoxia, and the late-stage renal tubular HIF-2α activation exerts protective effects against renal fibrosis. However, its specific role in progressive renal fibrosis remains unclear. Here, we investigated the effects of the long-term tubular activation of HIF-2α on renal function and fibrosis, using in vivo and in vitro models of renal fibrosis. Progressive renal fibrosis was induced in renal tubular epithelial cells (TECs) of tetracycline-controlled HIF-2α transgenic (Tg) mice and wild-type (WT) controls through a 6-week adenine diet. Tg mice were maintained on doxycycline (DOX) for the diet period to induce Tg HIF-2α expression. Primary TECs isolated from Tg mice were treated with DOX (5 ㎍/ml), transforming growth factor-β1 (TGF-β1) (10 ng/ml), and a combination of both for 24, 48, and 72 hr. Blood was collected to analyze creatinine (Cr) and blood urea nitrogen (BUN) levels. Pathological changes in the kidney tissues were observed using hematoxylin and eosin, Masson's trichrome, and Sirius Red staining. Meanwhile, the expression of fibronectin, E-cadherin and α-smooth muscle actin (α-SMA) and the phosphorylation of p38 mitogen-activated protein kinase (MAPK) was observed using western blotting. Our data showed that serum Cr and BUN levels were significantly lower in Tg mice than in WT mice following the adenine diet. Moreover, the protein levels of fibronectin and E-cadherin and the phosphorylation of p38 MAPK were markedly reduced in the kidneys of adenine-fed Tg mice. These results were accompanied by attenuated fibrosis in Tg mice following adenine administration. Consistent with these findings, HIF-2α overexpression significantly decreased the expression of fibronectin in TECs, whereas an increase in α-SMA protein levels was observed after TGF-β1 stimulation for 72 hr. Taken together, these results indicate that long-term HIF-2α activation in CKD may inhibit the progression of renal fibrosis and improve renal function, suggesting that long-term renal HIF-2α activation may be used as a novel therapeutic strategy for the treatment of CKD.

• Journal of Ginseng Research
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• v.45 no.3
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• pp.408-419
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• 2021

Background: The decreased renal function is known to be associated with biological aging, of which the main pathological features are chronic inflammation and renal interstitial fibrosis. In previous studies, we reported that total saponins from Panax japonicus (SPJs) can availably protect acute myocardial ischemia. We proposed that SPJs might have similar protective effects for aging-associated renal interstitial fibrosis. Thus, in the present study, we evaluated the overall effect of SPJs on renal fibrosis. Methods: Sprague-Dawley (SD) aging rats were given SPJs by gavage beginning from 18 months old, at 10 mg/kg/d and 60 mg/kg/d, up to 24 months old. After the experiment, changes in morphology, function and fibrosis of their kidneys were detected. The levels of serum uric acid (UA), β2-microglobulin (β2-MG) and cystatin C (Cys C) were assayed with ELISA kits. The levels of extracellular matrix (ECM), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), inflammatory factors and changes of oxidative stress parameters were examined. Results: After SPJs treatment, SD rats showed significantly histopathological changes in kidneys accompanied by decreased renal fibrosis and increased renal function; As compared with those in 3-month group, the levels of serum UA, Cys C and β2-MG in 24-month group were significantly increased (p < 0.05). Compared with those in the 24-month group, the levels of serum UA, Cys C and β2-MG in the SPJ-H group were significantly decreased. While ECM was reduced and the levels of MMP-2 and MMP-9 were increased, the levels of TIMP-1, TIMP-2 and transforming growth factor-β1 (TGF-β1)/Smad signaling were decreased; the expression level of phosphorylated nuclear factor kappa-B (NF-κB) was down-regulated with reduced inflammatory factors; meanwhile, the expression of nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling was aggrandized. Conclusion: These results suggest that SPJs treatment can improve age-associated renal fibrosis by inhibiting TGF-β1/Smad, NFκB signaling pathways and activating Nrf2-ARE signaling pathways and that SPJs can be a potentially valuable anti-renal fibrosis drug.

• BMB Reports
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• v.53 no.11
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• pp.594-599
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• 2020

Lin28a has diverse functions including regulation of cancer, reprogramming and regeneration, but whether it promotes injury or is a protective reaction to renal injury is unknown. We studied how Lin28a acts in unilateral ureteral obstruction (UUO)-induced renal fibrosis following unilateral ureteral obstruction, in a mouse model. We further defined the role of Lin28a in transforming growth factor (TGF)-signaling pathways in renal fibrosis through in vitro study using human tubular epithelium-like HK-2 cells. In the mouse unilateral ureteral obstruction model, obstruction markedly decreased the expression of Lin28a, increased the expression of renal fibrotic markers such as type I collagen, α-SMA, vimentin and fibronectin. In TGF-β-stimulated HK-2 cells, the expression of Lin28a was reduced and the expression of renal fibrotic markers such as type I collagen, α-SMA, vimentin and fibronectin was increased. Adenovirus-mediated overexpression of Lin28a inhibited the expression of TGF-β-stimulated type I collagen, α-SMA, vimentin and fibronectin. Lin28a inhibited TGF-β-stimulated SMAD3 activity, via inhibition of SMAD3 phosphorylation, but not the MAPK pathway ERK, JNK or p38. Lin28a attenuates renal fibrosis in obstructive nephropathy, making its mechanism a possible therapeutic target for chronic kidney disease.

• Korean Journal of Food Science and Technology
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• v.53 no.5
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• pp.561-569
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• 2021

Diabetic nephropathy is a major and representative complication of type 2 diabetes. Hyperglycemia increases the incidence of diabetic nephropathy, and induces kidney inflammation, thereby causing renal fibrosis, which is an important factor in the pathogenesis of diabetic nephropathy. This study investigated the effects of blackcurrant extract (BLC), which has been implicated in diabetic nephropathy in db/db mice, on glomerular fibrosis and renal dysfunction. The results showed that BLC consumption in type 2 diabetic db/db mice ameliorated diabetes-related metabolic disorders, such as insulin resistance and renal dysfunction, and significantly attenuated renal inflammation and renal fibrosis in diabetic nephropathy. In conclusion, these findings suggest that BLC consumption may help prevent renal fibrosis, inflammation, and consequent diabetic nephropathy.

• Biomolecules & Therapeutics
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• v.29 no.1
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• pp.41-51
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• 2021

Src family kinases (SFKs), an important group of non-receptor tyrosine kinases, are suggested to be excessively activated during various types of tissue fibrosis. The present study investigated the effect of KF-1607, an orally active and a newly synthesized Src kinase inhibitor (SKI) with proposed low toxicity, in preventing the progression of renal interstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed in 6-week-old male C57BL/6 mice to induce renal interstitial fibrosis. Either KF-1607 (30 mg/kg, oral gavage) or PP2 (2 mg/kg, intraperitoneal injection), a common experimental SKI, was administered to mice for seven days, started one day prior to surgery. UUO injury-induced SFK expression, including Src, Fyn, and Lyn kinase. SFK inhibition by KF-1607 prevented the progression of tubular injury in UUO mice, as indicated by decreases in albuminuria, urinary KIM-1 excretion, and kidney NGAL protein expression. Renal tubulointerstitial fibrosis was attenuated in response to KF-1607, as shown by decreases in α-SMA, collagen I and IV protein expression, along with reduced Masson's trichrome and collagen-I staining in kidneys. KF-1607 also inhibited inflammation in the UUO kidney, as exhibited by reductions in F4/80 positive-staining and protein expression of p-NFκB and ICAM. Importantly, the observed effects of KF-1607 were similar to those of PP2. A new pan Src kinase inhibitor, KF-1607, is a potential pharmaceutical agent to prevent the progression of renal interstitial fibrosis.

• Childhood Kidney Diseases
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• v.21 no.2
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• pp.47-52
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• 2017

Purpose: Renal ultrasonography has been widely used in children with renal disease. However, the relationship of renal echogenicity with renal pathology and function in children is not well known. Method: Ultrasound examination was performed in 75 patients undergoing renal biopsy for suspected renal disease in Konkuk University Medical Center from August 2005 to November 2015. We compared renal echogenicity to pathologic findings and renal function. Renal echogenicity was scored as 0 to 2 by comparing adjacent liver echogenicity. Three histologic characteristics were evaluated: glomerular changes, interstitial infiltration or fibrosis, and tubular atrophy. These were graded as 0 to 3, according to increasing severity. Laboratory results included urine albumin excretion and estimated glomerular filtration rate (eGFR). Results: Among pathologic findings, renal echogenicity revealed a positive correlation with interstitial infiltration or fibrosis (r=0.259, P=0.025), and with tubular atrophy (r=0.268, P=0.02). Renal echogenicity and glomerular changes were not correlated. Renal echogenicity showed a positive correlation with microalbuminuria (r=0.283, P=0.014), but a negative correlation with eGFR (r=-0.352, P=0.002). Conclusion: Increased renal echogenicity suggested severe interstitial infiltration or fibrosis and tubular atrophy among the pathologic findings. Moreover, increased echogenicity is correlated with increased urine albumin excretion and decreased eGFR. Echogenicity on ultrasonography is useful for determining the status of renal pathology and function.

• Korean Journal of Radiology
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• v.21 no.5
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• pp.588-597
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• 2020

Objective: To investigate the value of combined chemical exchange saturation transfer (CEST) and conventional magnetization transfer imaging (MT) in detecting metabolic and structural changes of renal fibrosis in rats with unilateral ureteral obstruction (UUO) at 3T MRI. Materials and Methods: Thirty-five Sprague-Dawley rats underwent UUO surgery (n = 25) or sham surgery (n = 10). The obstructed and contralateral kidneys were evaluated on days 1, 3, 5, and 7 after surgery. After CEST and MT examinations, ¹⁸F-labeled fluoro-2-deoxyglucose positron emission tomography was performed to quantify glucose metabolism. Fibrosis was measured by histology and western blots. Correlations were compared between asymmetrical magnetization transfer ratio at 1.2 ppm (MTR_asym(1.2ppm)) derived from CEST and maximum standard uptake value (SUV_max) and between magnetization transfer ratio (MTR) derived from MT and alpha-smooth muscle actin (α-SMA). Results: On days 3 and 7, MTR_asym(1.2ppm) and MTR of UUO renal cortex and medulla were significantly different from those of contralateral kidneys (p < 0.05). On day 7, MTR_asym(1.2ppm) and MTR of UUO renal cortex and medulla were significantly different from those of sham-operated kidneys (p < 0.05). The MTR_asym(1.2ppm) of UUO renal medulla was fairly negatively correlated with SUV_max (r = -0.350, p = 0.021), whereas MTR of UUO renal medulla was strongly negatively correlated with α-SMA (r = -0.744, p < 0.001). Conclusion: CEST and MT could provide metabolic and structural information for comprehensive assessment of renal fibrosis in UUO rats in 3T MRI and may aid in clinical monitoring of renal fibrosis in patients with chronic kidney disease.

• Herbal Formula Science
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• v.21 no.1
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• pp.154-160
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• 2013

Objectives : To investigate the therapeutic effect and underlying mechanisms of rhein on renal fibrosis in diabetic rats. Methods : Diabetic nephropathy (DN) was induced in adult Wistar rats via introperitoneal injection of streptozotocin (STZ) (20 mg/kg/d) for three consecutive days. Two days after the last dose of STZ, rhein was administered to the diabetic rats at a dose of 25 mg/kg or 50 mg/kg, twice a day by gavage, respectively. Following 28 days treatment with rhein, the plasma glucose and creatinine levels were measured, the renal levels of TGF-${\beta}1$ protein and mRNA were examined, and the fibronectin mRNA levels were also determined. Results : Rhein significantly inhibited the increased plasma glucose and creatinine levels of diabetic rats in a dose- and a time-dependent way. Immunohistochemical analysis showed both doses of rhein markedly attenuated elevated induction of renal TGF-${\beta}1$ protein expressions in diabetic rats. Additionally, the high dose of rhein improved both TGF-${\beta}1$ and fibronectin mRNA expressions, while the low dose of rhein only alleviated fibronectin mRNA expressions. Conclusions : Rhein can improve renal fibrosis in diabetic nephropathy rats, and which may be mediated through inhibition of the renal mRNA expressions of TGF-${\beta}1$ and fibronectin.

• Clinical and Experimental Pediatrics
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• v.45 no.7
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• pp.923-927
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• 2002

Congenital hepatic fibrosis is a relatively rare disease, characterized by bile ductular proliferation and prominent fibrosis in the portal area of liver resulting in portal hypertension. It is frequently associated with other abnormalities such as polycystic kidney, Caroli syndrome, cystic dysplasia of pancreas, intestinal lymphangiectasia, pulmonary emphysema, hemangioma, and cleft palate. We report here a case of congenital hepatic fibrosis associated with renal tubular ectasia in a 3-year-old girl, whose chief complaint was abdominal distension. Her liver function test did not reveal any abnormal findings. Hepatosplenomegaly and multiple dilated bile ducts were seen in the abdominal CT scaning. Esophageal varix was not detected by an endoscopic examination. Microscopically, diffuse portal fibrosis and widening with proliferation of blie ductules in the liver specimen and tubular ectasia in renal cortex were seen.