BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.
Amides/*pharmacology ; Angiotensin II/pharmacology ; Animals ; Disease Models, Animal ; Fibrosis ; Fumarates/*pharmacology ; Kidney/*drug effects/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis, Interstitial/genetics/metabolism/pathology/*prevention & control ; RNA, Messenger/genetics/metabolism ; Renin/*antagonists & inhibitors/metabolism ; Renin-Angiotensin System/*drug effects ; Toll-Like Receptor 2/deficiency/drug effects/genetics/*metabolism ; Ureteral Obstruction/*drug therapy/genetics/metabolism/pathology

Megalocytic interstitial nephritis is a rare form of kidney disease caused by chronic inflammation. We report a case of megalocytic interstitial nephritis occurring in a 45-yrold woman who presented with oliguric acute kidney injury and acute pyelonephritis accompanied by Escherichia coli bacteremia. Her renal function was not recovered despite adequate duration of susceptible antibiotic treatment, accompanied by negative conversion of bacteremia and bacteriuria. Kidney biopsy revealed an infiltration of numerous histiocytes without Michaelis-Gutmann bodies. The patient's renal function was markedly improved after short-term treatment with high-dose steroid.
Acute Disease ; Acute Kidney Injury/complications/*drug therapy/pathology ; Anti-Bacterial Agents/therapeutic use ; Azithromycin/therapeutic use ; Bacteremia/*drug therapy/microbiology/pathology ; Cefotaxime/therapeutic use ; Creatinine/blood ; Escherichia coli ; Escherichia coli Infections/*drug therapy/microbiology/pathology ; Female ; Humans ; Kidney/pathology ; Methylprednisolone/therapeutic use ; Middle Aged ; Nephritis, Interstitial/*drug therapy/immunology/pathology ; Pyelonephritis/complications/*drug therapy/pathology ; Renal Dialysis ; Shock, Septic/drug therapy/microbiology

Infliximab is a chimeric anti-tumor necrosis factor-alpha monoclonal antibody. Infusion related reactions and infection are well known side effects of infliximab; however, renal complications have not been well recognized. We report on a patient with late onset-acute tubulointerstitial nephritis (ATIN) after treatment with infliximab and mesalazine for Crohn's disease. A 25-year-old woman was admitted with a purpuric rash on both lower extremities and arthralgia. She had been diagnosed with Crohn's disease 5.6 years previously and had been treated with mesalazine and infliximab. Serum creatinine level, last measured one year ago, was elevated from 0.6 mg/dL to 1.9 mg/dL. Results of urinalysis, ultrasound, and serologic examinations were normal. With a tentative diagnosis of Henoch-Schonlein purpura, oral prednisolone was given, and serum creatinine decreased to 1.46 mg/dL, but was elevated to 2.6 mg/dL again at two months after discontinuation of prednisolone. Renal biopsy indicated that ATIN was probably induced by drug, considering significant infiltration of eosinophils. Concomitant use of infliximab with mesalazine was supposed to trigger ATIN. Oral prednisolone was administered, and serum creatinine level showed partial recovery. Thus, ATIN should be suspected as a cause of renal impairment in Crohn's disease even after a long period of maintenance treatment with infliximab and mesalazine.
Adalimumab/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Creatine/blood ; Crohn Disease/*drug therapy ; Drug Therapy, Combination ; Eosinophils/immunology ; Female ; Humans ; Infliximab/*adverse effects/*therapeutic use ; Kidney/pathology ; Mesalamine/*adverse effects/*therapeutic use ; Nephritis, Interstitial/*diagnosis/drug therapy/*etiology ; Prednisolone/therapeutic use

Hepatitis A virus (HAV) infection is generally a self-limited disease, but the infection in adults can be serious, to be often complicated by acute kidney injury (AKI) and rarely by virus-associated hemophagocytic syndrome (VAHS). Our patient, a 48-yr-old man, was diagnosed with HAV infection complicated by dialysis-dependent AKI. His kidney biopsy showed acute tubulointerstitial nephritis with massive infiltration of activated macrophages and T cells, and he progressively demonstrated features of VAHS. With hemodialysis and steroid treatment, he was successfully recovered.
Acute Disease ; Acute Kidney Injury/diagnosis/therapy ; Antibodies, Viral/analysis ; Hepatitis A/complications/*diagnosis/immunology ; Humans ; Lymphohistiocytosis, Hemophagocytic/complications/*diagnosis/pathology ; Macrophages/immunology ; Male ; Middle Aged ; Nephritis, Interstitial/complications/*diagnosis ; Renal Dialysis ; T-Lymphocytes/immunology

Adenovirus Infections, Human ; pathology ; virology ; Glomerulonephritis, Membranous ; pathology ; virology ; HIV Infections ; pathology ; virology ; Hepatitis B ; pathology ; virology ; Hepatitis C ; pathology ; virology ; Herpes Zoster ; pathology ; virology ; Herpesvirus 3, Human ; isolation & purification ; Humans ; Kidney ; pathology ; virology ; Kidney Diseases ; pathology ; virology ; Nephritis, Interstitial ; pathology ; virology ; Parvoviridae Infections ; pathology ; virology ; Parvovirus B19, Human ; isolation & purification

BACKGROUNDIt was reported that combination of mycophenolate mofetil (MMF) and enalapril could reduce proteinuria, improve renal function, and down-regulate diabetes-induced macrophage recruitment and expression of monocyte chemotactic protein 1 (MCP-1) and transforming growth factor beta (TGF-beta) in diabetic renal tissue. But there are no compelling data available for the combination of MMF and angiotensin converting enzyme inhibitor (ACEI) for suppressing tubulointerstitial fibrosis in chronic kidney diseases. The present study was to disclose the effect of MMF combined with benazapril on delaying tubulointerstitial fibrosis and its possible mechanisms in 5/6 nephrectomized rats.

METHODSFifty male SD rats underwent 5/6 nephrectomy (5/6 NX) were randomized into the following groups: NX (5/6 nephrectomized rats, distilled water, n = 10), MMF (MMF 20 mg x kg(-1) x d(-1), p.o., n = 10), Ben (benazepril 10 mg x kg(-1) x d(-1), p.o., n = 10), MMF/Ben (MMF 20 mg x kg(-1) x d(-1), p.o., and benazapril 10 mg x kg(-1) x d(-1), p.o., n = 10). They were monitored for proteinuria and systolic blood pressure every two weeks. After 8 weeks of treatment, serum creatinine and blood urea nitrogen were assayed and pathological damage to the kidney were evaluated. Renal expression and serum levels of platelet-derived growth factor-BB (PDGF-BB), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metaloproteinase-1 (TIMP-1) were detected by immunohistochemistry and ELISA methods.

RESULTSAfter 8 weeks of treatment, 24-hour proteinuria, serum creatinine and blood urea nitrogen were significantly lower in treated groups compared with the untreated rats. MMF and benazepril combination therapy had a greater effect than either drug alone. MMF alone had no effect on systolic blood pressure, but benazapril and MMF/benazapril could significantly reduce blood pressure. Rats that underwent 5/6 nephrectomy had greater tubulointerstitial inflammatory cell infiltration and collagen accumulation than sham-operated rats; all treatments, especially MMF/benazepril, ameliorated these effects. Tubules in 5/6 nephrectomized rats expressed higher levels of PDGF-BB and TIMP-1 and lower MMP-9 compared with sham-operated rats. MMF and benazepril similarly reversed these phenomenons and combination therapy almost completely restored the expression of these cytokines in renal tissue and their plasma concentration.

CONCLUSIONSMMF, especially combined with benazepril, can reduce proteinuria, improve renal function, ameliorate tubulointerstitial fibrosis in 5/6 nephrectomized rats. These effects might be, in part, associated with down-regulation of PDGF-BB and TIMP-1, and MMP-9 up-regulation in renal tissues.

Animals ; Benzazepines ; therapeutic use ; Enzyme-Linked Immunosorbent Assay ; Immunohistochemistry ; Immunosuppressive Agents ; therapeutic use ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Mycophenolic Acid ; analogs & derivatives ; therapeutic use ; Nephrectomy ; Nephritis, Interstitial ; drug therapy ; metabolism ; pathology ; Platelet-Derived Growth Factor ; metabolism ; Proto-Oncogene Proteins c-sis ; Rats ; Rats, Sprague-Dawley ; Tissue Inhibitor of Metalloproteinase-1 ; metabolism

OBJECTIVE: To observe the expression of plasma thrombospondin-1(TSP-1) at different time in protein-overload rats and to analyze the relationship between plasma TSP-1 expression and renal interstitial fibrosis. METHODS: Forty-five male Sprague-Dawley rats were randomly divided into a bovine serum albumin (BSA) group and a control group after uninephrectomization. Rats with protein overload nephropathy induced by intraperitoneally injected BSA were used as a model (control group received saline). At the 1st, 5th, and 9th weekend, the level of 24 h proteinuria and renal function was assessed. Pathological changes were observed by electron and fluorescent microscopy. The expression of plasma TSP-1 was detected by Western blot. The relationship between plasma TSP-1 and tubulointerstitial lesions (TIL) score was analyzed. RESULTS: Twenty-four hour proteinuria and blood urea nitrogen (BUN) significantly increased in protein-overload rats compared with those in the control group. While protein-overload rats developed more severe fibrosis in the tubular and interstitium. Glomerulosclerosis index and TIL score were upregulated compared with those in the control group. The expression of TSP-1 increased significantly at the 5th and 9th weekend. The expression of TSP-1 was positively correlated with TIL score (r=0.836, P<0.01). CONCLUSION Plasma TSP-1 expression is positively correlated with renal interstitial fibrosis in protein-overload rats. Plasma TSP-1 may be used for an important biomarker of renal interstitial fibrosis.
Animals ; Fibrosis ; metabolism ; pathology ; Glomerulosclerosis, Focal Segmental ; pathology ; Kidney ; metabolism ; pathology ; Male ; Nephrectomy ; Nephritis, Interstitial ; etiology ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley ; Thrombospondin 1 ; blood

Total saponins of Panax notoginseng (PNS) have been shown to ameliorate renal interstitial fibrosis. Ginsenoside Rg1, a panaxatriol saponin, is one of the major active molecules from PNS. The present study was undertaken to investigate the effect of ginsenoside Rg1 on renal fibrosis in rats with unilateral ureteral obstruction (UUO). The rats were randomly divided into 3 groups: sham-operation (n=15), UUO (n=15) and UUO with ginsenoside Rg1 treatment (n=15, 50 mg per kg body weight, intraperitoneally (i.p.) injected). The rats were sacrificed on Days 7 and 14 after the surgery. Histological examination demonstrated that ginsenoside Rg1 significantly inhibited interstitial fibrosis including tubular injury as well as collagen deposition. alpha-smooth muscle actin (alpha-SMA) and E-cadherin are two markers of tubular epithelial-myofibroblast transition (TEMT). Interestingly, ginsenoside Rg1 notably decreased alpha-SMA expression and simultaneously enhanced E-cadherin expression. The messenger RNA (mRNA) of transforming growth factor-beta1 (TGF-beta1), a key mediator to regulate TEMT, in the obstructed kidney increased dramatically, but was found to decrease significantly after administration of ginsenoside Rg1. Further study showed that ginsenoside Rg1 considerably decreased the levels of both active TGF-beta1 and phosphorylated Smad2 (pSmad2). Moreover, ginsenoside Rg1 substantially suppressed the expression of thrombospondin-1 (TSP-1), a cytokine which can promote the transcription of TGF-beta1 mRNA and the activation of latent TGF-beta1. These results suggest that ginsenoside Rg1 inhibits renal interstitial fibrosis in rats with UUO. The mechanism might be partly related to the blocking of TEMT via suppressing the expression of TSP-1.
Actins ; biosynthesis ; Animals ; Cadherins ; biosynthesis ; Collagen Type I ; genetics ; metabolism ; Fibronectins ; genetics ; metabolism ; Ginsenosides ; pharmacology ; Immunohistochemistry ; Male ; Nephritis, Interstitial ; drug therapy ; genetics ; metabolism ; pathology ; Panax notoginseng ; chemistry ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Smad2 Protein ; biosynthesis ; Thrombospondin 1 ; biosynthesis ; genetics ; Transforming Growth Factor beta1 ; biosynthesis ; genetics ; Ureteral Obstruction ; metabolism ; pathology

OBJECTIVETo study the effect of Kurarinone on renal tubular epithelial cell-mesenchyma (ECM) trans-differentiation in rats with renal interstitial fibrosis and to explore its possible mechanisms.

METHODSThe rat model of renal interstitial fibrosis was established by unilateral ureteral obstruction (UUO). Sprague-Dawley male rats were randomly divided into 3 groups, the sham-operated group, the UUO group and the Kurarinone treated group (KTG). Rats in the KTG were intraperitoneally injected with Kurarinone 100 mg/kg daily after modeling. Five rats of each group were killed respectively at day 7, 14 and 21 after UUO. The serum levels of blood urea nitrogen (BUN), serum creatinine (SCr), total protein (TP) and albumin (ALB), 24-h urinary protein excretion in rats were measured. Pathological changes of renal tissue were observed by PAS and Masson stain. The expression of transforming growth factor beta1 (TGF-beta1), Smad3, alpha-smooth muscle actin (alpha-SMA) and collagen I (Col I) in kidney were determined with immunohistochemistry. And the expressions of TGF-beta1 and alpha-SMA mRNA in renal tissue were determined using reverse transcription polymerase chain reaction (RT-PCR).

RESULTSThe expression of TGF-beta1, Smad3, alpha-SMA and Col I in the KTG was significantly decreased as compared with that in the UUO group respectively, and the degree of tubular damage and renal interstitial fibrosis was also ameliorated more obviously in the KTG. The TGF-beta1 and alpha-SMA mRNA expressions in KTG were significantly lower than those in the UUO group determined at the corresponding time points (P < 0.05).

CONCLUSIONKurarinone could down-regulate the expression of TGF-beta1 and Col I, inhibit EC-M trans-differentiation, suppress the activation and proliferation of myofibroblast. The probable pathway may be by way of down-regulating Smad3 expression to interfere its induction on intercellular signal transduction and consequently ameliorate renal interstitial fibrosis.

Animals ; Cell Transdifferentiation ; drug effects ; Collagen Type I ; biosynthesis ; genetics ; Epithelial Cells ; drug effects ; metabolism ; pathology ; Fibrosis ; Flavonoids ; pharmacology ; Immunohistochemistry ; Kidney ; drug effects ; metabolism ; pathology ; Kidney Tubules ; drug effects ; metabolism ; pathology ; Male ; Mesoderm ; drug effects ; metabolism ; pathology ; Nephritis, Interstitial ; physiopathology ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Transforming Growth Factor beta1 ; biosynthesis ; genetics

Adolescent ; Child ; Humans ; Male ; Nephritis, Interstitial ; pathology ; Uveitis ; pathology