• BMB Reports
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• v.52 no.9
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• pp.554-559
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• 2019

Despite reports suggesting that tissue-resident natural killer (trNK) cells cause ischemic kidney injury, their contribution to the development of tubulointerstitial fibrosis has not been determined. This study hypothesized that the depletion of trNK cells may ameliorate renal fibrosis by affecting transglutaminase 2/syndecan-4 interactions. Aristolochic acid nephropathy (AAN) was induced in C57BL/6 mice as an experimental model of kidney fibrosis. The mice were treated with anti-asialo GM1 (ASGM1) or anti-NK1.1 antibodies to deplete NK cells. Although both ASGM1 and NK1.1 antibodies suppressed renal $NKp46^+DX5^+$ NK cells, renal $NKp46^+DX5^-$ cells were resistant to suppression by ASGM1 or NK1.1 antibodies during the development of tubulointerstitial fibrosis in the AAN-induced mouse model. Western blot analysis showed that both antibodies increased the expression of fibronectin, transglutaminase 2, and syndecan-4. These findings indicate that trNK cells played an exacerbating role in tubulointerstitial fibrosis by activating transglutaminase 2 and syndecan-4 in the AAN-induced mouse model.

• 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.

• 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.20 no.2
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• pp.83-87
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• 2016

Congenital chloride diarrhea (CLD) is a rare autosomal recessive disease that is difficult to diagnose. CLD requires early treatment to correct electrolyte imbalance and alkalosis and to prevent severe dehydration. Renal injury is clearly associated with defective electrolyte balance induced by CLD, particularly during the first months or years of life. A 7-year-old boy was diagnosed with CLD following detection of a homozygous mutation (c.2063-1G>T) in SLC26A3 at 6 months of age. During treatment with electrolyte supplements, mild proteinuria was detected at 8 months of age, and is still present. Renal biopsy showed the presence of focal renal dysplasia, with metaplastic cartilage and mononuclear cell infiltration, calcification, and fibrosis in the interstitium. Up to two-thirds of the glomeruli exhibited global obsolescence, mostly aggregated in the dysplastic area. In nondysplastic areas, the glomeruli were markedly increased in size and severely hypercellular, with increased mesangial matrix, and displayed segmental sclerosis. The marked glomerular hypertrophy with focal segmental glomerulosclerosis suggested a compensatory reaction to the severe nephron loss or glomerular obsolescence associated with renal dysplasia, with superimposed by CLD aggravating the tubulointerstitial damage.

• Childhood Kidney Diseases
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• v.23 no.1
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• pp.48-52
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• 2019

The ketogenic diet (KD) has been used as an effective antiepileptic therapy for intractable childhood epilepsy. However, various adverse effects have been reported with use of the KD. We report a case of a child who developed acute tubular necrosis subsequent to therapy with KD. A 5-year-old girl had myoclonic epilepsy with developmental delay. She was under the treatment with antiepileptic drugs since the age of 3 months and on the KD during the past 18 months. Proteinuria persisted intermittently with the initiation of the KD and subsequently increased in the past 2 months. She was admitted with intermittent mild fever, vomiting, and lethargy for the past 3-4 weeks. At the time of admission, she presented with hypertriglyceridemia, heavy proteinuria, renal Fanconi syndrome, and acute kidney injury. Renal sonography showed a marked increase in the size and parenchymal echogenicity of both kidneys. A renal biopsy revealed acute tubular necrosis accompanied by early interstitial fibrosis. After the withdrawal of the KD and supportive therapy, without changing other anticonvulsants and their dosages, improvement of renal function was observed. Proteinuria had disappeared after 1 month and kidney size returned to normal after 8 months. It is hypothesized that the KD can induce and/or aggravate the renal tubulointerstitial injury in some patients who are under the treatment with anticonvulsants.

• Childhood Kidney Diseases
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• v.13 no.2
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• pp.99-117
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• 2009

Diabetic nephropathy is a major cause of chronic renal failure in developing countries, and the prevalence rate has markedly increased during the past decade. Diabetic nephropathy shows various specific histological changes not only in the glomeruli but also in the tubulointerstitial region. In the early stage, the effacement of podocyte foot processes and thickened glomerular basement membrane (GBM) is noticed even at the stage of microalbuminuria. Nodular, diffuse, and exudative lesions, so-called diabetic glomerulosclerosis, are well known as glomerular lesions. Interstitial lesions also exhibit fibrosis, edema, and thickened tubular basement membrane. Diabetic nephropathy is considered to be multifactorial in origin with increasing evidence that one of the major pathways involved in the development and progression of diabetic nephropathy as a result of hyperglycemia. Hyperglycemia induces renal damage directly or through hemodynamic alterations, such as, glomerular hyperfiltration, shear stress, and microalbuminuria. Chronic hyperglycemia also induces nonhemodynamic dysregulations, such as, increased production of advanced glycosylation endproducts, oxidative stress, activation of signal pathway, and subsequent various cytokines. Those pathogenic mechanisms resulted in extracellular matrix deposition including mesangial expansion and GBM thickening, glomerular hypertrophy, inflammation, and proteinuria. In this review, recent opinions on the histopathologic changes and pathophysiologic mechanisms leading to initiation and progression of diabetic nephropathy will be introduced.

• Korean Journal of Transplantation
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• v.28 no.3
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• pp.135-143
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• 2014

Background: Kidney injury molecule-1 (KIM-1) is known as a good ancillary marker of acute kidney injury (AKI) and its expression has also been observed in acute rejection and chronic graft dysfunction. We tested usefulness of KIM-1 as an indicator of acute and chronic renal graft injury by correlating KIM-1 expression with renal graft function and histology. Methods: A total of 133 zero-time biopsies and 42 follow-up biopsies obtained within 1 year posttransplantation were selected. Renal tubular KIM-1 staining was graded semiquantitatively from 0 to 3 and the extent of staining was expressed as the ratio of KIM-1 positive/CD10 positive proximal tubules using Image J program. Results: KIM-1 was positive in 39.8% of zero-time biopsies. KIM-1 positive cases were predominantly male and had received grafts from donors with older age, deceased donors, and poor renal function at the time of donation, compared with KIM-1 negative cases. KIM-1 expression showed correlation with delayed graft function and acute tubular necrosis. In comparison of KIM-1 expression between stable grafts (n=23) and grafts with dysfunction (n=19) at the time of repeated biopsy, the intensity/extent of KIM-1 staining and renal histology at zero-time did not differ significantly between the two groups. Histologically, KIM-1 expression was significantly increased with both acute and chronic changes of glomeruli, tubules and interstitium, peritubular capillaritis, and arteriolar hyalinosis. Conclusions: KIM-1 can be used as an ancillary marker of AKI and a nonspecific indicator of acute inflammation and tubulointerstitial fibrosis. However, KIM-1 expression at zero-time is not suitable for prediction of long-term graft dysfunction.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.18 no.3
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• pp.87-94
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• 2018

We present the case of long-term observation of a patient with chronic kidney disease (CKD) caused by advanced focal segmental glomerulosclerosis (FSGS) resulting from underlying congenital chloride diarrhea (CLD). A 20-year-old woman was admitted for prolonged proteinuria despite conservative treatment for CLD. She was diagnosed with CLD and started taking KCl salt supplementation from the time of birth. Mild proteinuria was first found at 12 years of age, which progressed to moderate proteinuria at 16 years of age. At 16 years of age, CKD stage 2 with FSGS was diagnosed based on the initial assessment of the glomerular filtration rate (GFR) and kidney histology. On admission, we re-assessed her renal function, histology and genetic analysis. GFR had deteriorated to CKD stage 4 and renal histology revealed an advanced FSGS combined with tubulointerstitial fibrosis. A homozygous mutation in the SLC26A3 gene (c.2063-1G>T) was found by diagnostic exome sequencing and may have been inherited from both parents. CLD patients can be more vulnerable to renal injury, which may also cause progression of renal failure. Therefore, even if there is an early diagnosis and adequate salt supplementation, close monitoring of renal function and tailored treatment should be emphasized for renal protection and favorable CLD prognosis.