Effects of nitric oxide on renal interstitial fibrosis in rats with unilateral ureteral obstruction

AimsIt is well recognized that microvascular injury is a major determinant of renal fibrosis. Mounting evidence shows that nitric oxide (NO) plays an important role in angiogenesis. Therefore, we investigated to the effects of NO on kidney angiogenesis and renal fibrosis.MethodsIn the present study, a unilateral ureteral obstruction (UUO) model was established with l-arginine (l-Arg, 1 g/dl) and N-nitro-l-arginine methyl ester (L-NAME, 5 mg/dl) serving as interference factors. We investigated the alteration of NO concentration with spectrophotometry, peritubular capillary (PTC) density with aminopeptidase P (JG12) immunohistochemical staining, and the expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), hypoxia inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1) with immunohistochemical staining and Western blotting at weeks 2, 3 and 4.Key findingsOur findings showed that the expressions of VEGF, eNOS and PTC density were significantly decreased in rats with UUO, which was accompanied by a progressive increase in HIF-1α, TGF-β1 and an area of renal interstitial fibrosis. The administration of l-Arg promoted the synthesis of NO and significantly elevated the expressions of VEGF, eNOS and PTC density with the conspicuous loss of HIF-1α and TGF-β1 expressions and ultimately ameliorated renal fibrosis, which was markedly aggravated by L-NAME administration.SignificanceThese findings demonstrate that NO appears to play an important role in kidney angiogenesis and in slowing the progression of renal interstitial fibrosis, which suggests that NO may serve as a novel therapeutic strategy for preventing renal fibrosis as well as fibrosis in other organs.     

依帕司他对单侧输尿管梗阻大鼠肾间质纤维化的干预作用及其机制

目的:观察依帕司他(EPS)对单侧输尿管梗阻(UUO)大鼠间质纤维化的保护作用及其机制。方法:实验设假手术组(Sham)组、UUO、UUO+EPS(50 mg/kg)及UUO+EPS(100 mg/kg)剂量组,每组n=8。左侧输尿管结扎制备UUO大鼠模型。造模后连续灌胃给药3周,sham和UUO组给予等体积的羟甲基纤维素钠。HE和Masson染色观察肾组织病理变化及胶原沉积情况。免疫组化法观察肾组织醛糖还原酶(AR)表达情况,分别采用real-time PCR和(或) Western blot检测肾脏I型胶原(collagen I)、III型胶原(collagen III)、α-平滑肌肌动蛋白(α-SMA)、成纤维细胞特异蛋白-1(FSP-1)、纤连蛋白(FN)、E-钙粘蛋白(E-cadherin)、转化生成因子-β1(TGF-β1)和AR mRNA及蛋白表达。结果:与Sham组相比,UUO组大鼠小管上皮细胞萎缩、空泡样变性,肾间质成纤维细胞及肌成纤维细胞大量增殖并伴大量炎症细胞浸润,胶原沉积明显增加,collagen I、collagen III、TGF-β1和AR mRNA及蛋白表达水平明显升高(P<0.01),同时EMT标志性蛋白α-SMA、FSP-1、FN mRNA及蛋白表达水平明显升高(P<0.01),而E-cadherin mRNA及蛋白表达水平明显降低。与UUO组相比,经EPS治疗3周后,肾间质纤维化程度明显减轻,胶原沉积明显减少,collagen I、collagen III、TGF-β1和AR mRNA及蛋白表达水平明显降低(P<0.01或P<0.05),另外α-SMA、FSP-1、FN mRNA及蛋白表达水平明显降低(P<0.01或P<0.05),而E-cadherin mRNA及蛋白表达水平明显升高(P<0.01或P<0.05),而且100 mg/kg剂量组上述指标的改变均好于低剂量组(P<0.05,P<0.01)。结论:依帕司他对肾间质纤维化具有一定的改善作用,其机制可能与其抑制TGF-β1介导的AR表达、进而抑制大鼠肾小管上皮细胞EMT有关。     

依那普利在大鼠单侧输尿管梗阻再通模型中的抗纤维化作用

目的:探讨依那普利对大鼠单侧输尿管梗阻再通模型肾脏纤维化的影响.方法:18只SD大鼠随机分为两组:假手术组(6只)以及单侧输尿管梗阻模型组(12只).输尿管梗阻3天后,实施梗阻再通手术,再将大鼠随机分为模型组(6只)以及依那普利组(6只),术后,依那普利组给予依那普利灌胃10mg/kg/d,假手术组以及模型组给予等量0.5%CM-CNa溶液灌胃.用药2周后,取术侧肾组织做HE染色,并采用Raford评分系统对肾间质损伤程度进行评分;用Real-timePCR方法检测Ⅰ、Ⅲ型胶原以及CT-GFmRNA的表达;用Westemblot方法检测CTGF蛋白水平的表达.结果:模型组大鼠肾脏损伤程度,Ⅰ、Ⅲ型胶原mRNA表达水平,以及CTGFmRNA和蛋白表达水平均比假手术组明显上升(P<0.01).经依那普利治疗后,与模型组相比,以上指标均显著下降(P<0.01).结论:依那普利能有效阻止大鼠单侧输尿管梗阻再通后肾脏纤维化的进展.依那普利抗纤维化的作用机制可能与抑制CTGF的表达有关.     

Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/α-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor β 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors.     

Transplantation of endothelial progenitor cells alleviates renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction

AimsThe present study investigated whether transplantation of bone marrow-derived endothelial progenitor cells (BM-EPCs) in renal capillary network improves renal interstitial fibrosis in unilateral ureteral obstruction (UUO) model in mice.Main methodsEx vivo generated, characterized, and cultivated mice BM-EPCs were identified by their vasculogenic properties in vitro. BM-EPCs were labelled with carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) before transplantation. The animal models of UUO were used. Histological changes in renal tubular interstitium were observed with HE and Masson staining. The protein levels of vascular endothelial growth factor(VEGF), hypoxia inducible factor-1α (HIF-1α) and connective tissue growth factor (CTGF) were analyzed by western blotting and immunohistochemistry. Transforming growth factor-β1 (TGF-β1) was detected by immunohistochemistry. Peritubular capillary (PTC) density was determined by CD31 immunostaining.Key findingsTransplanted BM-EPCs were successfully incorporated into the capillary network in the obstructed kidney in vivo. UUO induced a significant decrease in VEGF levels and PTC density in the kidney tissue, which was accompanied by a significant increase in HIF-1α, CTGF and TGF-β1. Transplantation of BM-EPCs increased PTC density, VEGF expression and alleviated the development of renal interstitial fibrosis in UUO mice. No significant pathological changes were found in control mice.SignificanceThe reduction of PTC density and up-regulation of HIF-1α are the important mechanisms of interstitial fibrosis in UUO mice. BM-EPCs transplantation may increase the number of capillary density and alleviate the development of renal fibrosis in obstructive nephropathy in mice.     

Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction

Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis.     

Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction

Poly(ADP-ribose) polymerase 1 (PARP1) contributes to necrotic cell death and inflammation in several disease models; however, the role of PARP1 in fibrogenesis remains to be defined. Here, we tested whether PARP1 was involved in the pathogenesis of renal fibrosis using the unilateral ureteral obstruction (UUO) mouse model. UUO was performed by ligation of the left ureter near the renal pelvis in Parp1-knockout (KO) and wild-type (WT) male mice. After 10 days of UUO, renal PARP1 expression and activation were strongly increased by 6- and 13-fold, respectively. Interstitial fibrosis induced by UUO was significantly attenuated in Parp1-KO kidneys compared with that in WT kidneys at 10 days, but not at 3 days, based on collagen deposition, α-smooth muscle actin (α-SMA), and fibronectin expression. Intriguingly, the UUO kidneys in Parp1-KO mice showed a dramatic decrease in infiltration of neutrophil and reduction in expression of proinflammatory proteins including intercellular adhesion molecule-1, tumor necrosis factor-α, inducible nitric oxide synthase, and toll-like receptor 4 as well as phosphorylation of nuclear factor-κB p65, but not transforming growth factor-β1 (TGF-β1) at both 3 and 10 days. Pharmacological inhibition of PARP1 in rat renal interstitial fibroblast (NRK-49F) cell line or genetic ablation in primary mouse embryonic fibroblast cells did not affect TGF-β1-induced de novo α-SMA expression. Parp1 deficiency significantly attenuated UUO-induced histological damage in the kidney tubular cells, but not apoptosis. These data suggest that PARP1 induces necrotic cell death and contributes to inflammatory signaling pathways that trigger fibrogenesis in obstructive nephropathy.     

Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis

Renal fibrosis is a common pathological process that occurs with diverse etiologies in chronic kidney disease. However, its regulatory mechanisms have not yet been fully elucidated. Ferroptosis is a form of non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. It is currently unknown whether ferroptosis is initiated during unilateral ureteral obstruction (UUO)-induced renal fibrosis and its role has not been determined. In this study, we demonstrated that ureteral obstruction induced ferroptosis in renal tubular epithelial cells (TECs) in vivo. The ferroptosis inhibitor liproxstatin-1 (Lip-1) reduced iron deposition, cell death, lipid peroxidation, and inhibited the downregulation of GPX4 expression induced by UUO, ultimately inhibiting ferroptosis in TECs. We found that Lip-1 significantly attenuated UUO-induced morphological and pathological changes and collagen deposition of renal fibrosis in mice. In addition, Lip-1 attenuated the expression of profibrotic factors in the UUO model. In vitro, we used RSL3 treatment and knocked down of GPX4 level by RNAi in HK2 cells to induce ferroptosis. Our results indicated HK2 cells secreted various profibrotic factors during ferroptosis. Lip-1 was able to inhibit ferroptosis and thereby inhibit the secretion of the profibrotic factors during the process. Incubation of kidney fibroblasts with culture medium from RSL3-induced HK2 cells promoted fibroblast proliferation and activation, whereas Lip-1 impeded the profibrotic effects. Our study found that Lip-1 may relieve renal fibrosis by inhibiting ferroptosis in TECs. Mechanistically, Lip-1 could reduce the activation of surrounding fibroblasts by inhibiting the paracrine of profibrotic factors in HK2 cells. Lip-1 may potentially be used as a therapeutic approach for the treatment of UUO-induced renal fibrosis.Subject terms: Cell death, RNAi, Urinary tract obstruction     

Mast cells are required for the development of renal fibrosis in the rodent unilateral ureteral obstruction model

Mast cells are associated with inflammation and fibrosis. Whether they protect against or contribute to renal fibrosis is unclear. Based on our previous findings that mast cells can express and secrete active renin, and that angiotensin (ANG II) is profibrotic, we hypothesized that mast cells play a critical role in tubulointerstitial fibrosis. We tested this hypothesis in the 14-day unilateral ureteral obstruction (UUO) model in rats and mast cell-deficient (MCD) mice (WBB6F1-W/Wv) and their congenic controls (CC). In the 14-day UUO rat kidney, mast cell number is increased and they express active renin. Stabilizing mast cells in vivo with administration of cromolyn sodium attenuated the development of tubulointerstitial fibrosis, which was confirmed by measuring newly synthesized pepsin-soluble collagen and blind scoring of fixed trichrome-stained kidney sections accompanied by spectral analysis. Fibrosis was absent in UUO kidneys from MCD mice unlike that observed in the CC mice. Losartan treatment reduced the fibrosis in the CC UUO kidneys. The effects of mast cell degranulation and renin release were tested in the isolated, perfused kidney preparation. Mast cell degranulation led to renin-dependent protracted flow recovery. This demonstrates that mast cell renin is active in situ and the ensuing ANG II can modulate intrarenal vascular resistance in the UUO kidney. Collectively, the data demonstrate that mast cells are critical to the development of renal fibrosis in the 14-day UUO kidney. Since renin is present in human kidney mast cells, our work identifies potential targets in the treatment of renal fibrosis.     

Ablation of Gadd45β ameliorates the inflammation and renal fibrosis caused by unilateral ureteral obstruction

The growth arrest and DNA damage‐inducible beta (Gadd45β) protein have been associated with various cellular functions, but its role in progressive renal disease is currently unknown. Here, we examined the effect of Gadd45β deletion on cell proliferation and apoptosis, inflammation, and renal fibrosis in an early chronic kidney disease (CKD) mouse model following unilateral ureteral obstruction (UUO). Wild‐type (WT) and Gadd45β‐knockout (KO) mice underwent either a sham operation or UUO and the kidneys were sampled eight days later. A histological assay revealed that ablation of Gadd45β ameliorated UUO‐induced renal injury. Cell proliferation was higher in Gadd45β KO mouse kidneys, but apoptosis was similar in both genotypes after UUO. Expression of pro‐inflammatory cytokines after UUO was down‐regulated in the kidneys from Gadd45β KO mice, whereas UUO‐mediated immune cell infiltration remained unchanged. The expression of pro‐inflammatory cytokines in response to LPS stimulation decreased in bone marrow‐derived macrophages from Gadd45β KO mice compared with that in WT mice. Importantly, UUO‐induced renal fibrosis was ameliorated in Gadd45β KO mice unlike in WT mice. Gadd45β was involved in TGF‐β signalling pathway regulation in kidney fibroblasts. Our findings demonstrate that Gadd45β plays a crucial role in renal injury and may be a therapeutic target for the treatment of CKD.     

The effect of unilateral ureteral obstruction on renal function in pigs measured by diffusion-weighted MRI

The objective of this study was to examine the effect of unilateral ureteral obstruction on the apparent diffusion coefficient (ADC) in pig kidney. Changes in ADC is suggested to reflect changes in the ratio of extracellular to intracellular volume. Thirteen pigs were allocated into three groups: 1) pigs subjected to acute unilateral ureteral obstruction (AUO) (n = 3), 2) pigs subjected to chronic partial unilateral obstruction (CPUO) (n = 3), and 3) control pigs (n = 7). The extra- to intracellular volume ratio was indirectly measured in both the ipsilateral obstructed kidney and contralateral non-obstructed kidney by the ADC of the renal tissue using diffusion-weighted echo-planar magnetic resonance imaging. ADC was 2.07 +/- 0.27 x 10(-3) mm2/s in the cortex and 2.10 +/- 0.24 x 10(-3) mm2/s in the medulla of normal control kidneys. In the obstructed kidney from the AUO group the ADC of the medulla was significantly reduced 24 hours after occlusion of the ureter (1.65 +/- 0.05 x 10(-3) mm2/s vs 2.10 +/- 0.24 x 10(-3) mm2/s; p < 0.05). Similarly ADC decreased slightly in the cortex of the ipsilateral kidney. In contrast, ADC of the ipsilateral kidney of CPUO pigs was increased both in the renal medulla (3.13 +/- 0.21 x 10(-3) mm2/s vs. 2.10 +/- 0.24 x 10(-3) mm2/s; p < 0.05) and cortex (3.09 +/- 0.14 x 10(-3) mm2/s vs. 2.07 x 10(-3) mm2/s, p < 0.05). In conclusion, the results of the present study suggest that diffusion weighted imaging (ADC) may be a useful parameter to incorporate when identifying whether a ureteric obstruction is acute or chronic.     

Altered phospholipid profile in urine of rats with unilateral ureteral obstruction

Little is known about renal damage to the contralateral kidney after unilateral ureteral obstruction (UUO). Using liquid chromatography-time of flight-mass spectrometry combined with principal component analysis (PCA), we compared urinary phospholipid profiles before and two weeks after UUO in rats. PCA revealed that negative ions corresponding to three molecular species of phosphatidylethanolamine (PE) and two species of phosphatidylglycerol (PG) had a higher score than other phospholipids such as phosphatidylcholine, phosphatidylinositol, and sphingomyelin. The assigned species of PE and PG were postulated to possess a monoenoic or dienoic fatty acyl group, and the ratios of their levels in urine from UUO to that in the controls were much higher than those having a highly polyunsaturated fatty acyl group. These results indicate that PE and PG having a monoenoic or dienoic fatty acyl group are potential biomarkers for injury of contralateral kidney after UUO.     

Effect of acute and chronic renal denervation on renal function after release of unilateral ureteral obstruction in the rat.

The role of the renal nerves in determining renal function after relief of 24-h unilateral ureteral obstruction (UUO) was studied using clearance techniques in anaesthetized rats. Acute renal denervation during the first 1--2 h after relief of UUO resulted in a significant increase in glomerular filtration rate (GFR), renal plasma flow (RPF), urine flow, and sodium and potassium excretion, changes which were not seen in the sham-denervated postobstructive kidney. Acute denervation of sham-operated normal kidneys caused a similar natriuresis and diuresis but with no change in GFR or RPF. Chronic renal denervation 4--5 days before UUO denervated postobstructive controls, while chronic denervation alone was associated with a significantly higher urine flow and sodium excretion rate from the denervated kidney. The effectiveness of renal denervation was confirmed by demonstrating marked depletion of tissue catecholamines in the denervated kidney. It was concluded that renal nerve activity plays a significant but not a major role in the functional changes present after relief of UUO. Chronic renal denervation did not protect against the functional effects of unilateral ureteral obstruction.     

基于超高效液相色谱质谱的药物性肝损害患者血清代谢组学研究

目的 应用代谢组学结合多变量统计学方法研究药物性肝损害患者血清当中的小分子代谢物质,寻找可用于药物性肝损害早期诊断的潜在生物标志物.方法 选择药物性肝损害患者26例和正常对照23例,应用非靶向的线性梯度超高效液相色谱质谱系统检测血清中的小分子代谢物质.结果 药物性肝损害组和对照组相比,血清中溶血卵磷脂C16∶0、溶血卵磷脂C18∶0、溶血卵磷脂C18∶3、溶血卵磷脂C18∶2的浓度明显降低,硬脂酰胺、油酰胺、十四酰胺、卵磷脂、甘氨鹅去氧胆酸、甘氨胆酸、胆红素、次黄嘌呤显著升高.结论 药物性肝损害患者代谢发生了显著的变化,根据代谢物质的变化有助于临床诊断,研究表明代谢组学是临床研究的一个强有力工具.     

Intervention effects of puerarin on blood stasis in rats revealed by a 1H NMR-based metabonomic approach

Puerarin possesses a wide spectrum of biological activities including ameliorating effects on blood stasis, but the definite mechanism of this effect is still not known. In this study, a ¹H NMR-based plasma and urinary metabonomic approach was applied to comprehensively and holistically investigate the therapeutic effects of puerarin on blood stasis and its underlying mechanisms. Puerarin was injected intraperitoneally once daily for consecutive 7 days. The blood stasis rat model was established by placing the rats in ice-cold water during the time interval between two injections of adrenaline. With pattern recognition analysis, a clear separation of blood stasis model group and healthy control group was achieved and puerarin pretreatment group was located much closer to the control group than the model group, which was consistent with results of hemorheology studies. 15 and 10 potential biomarkers associated with blood stasis in plasma and urine, respectively, which were mainly involved in energy metabolism, lipid and membrane metabolisms, amino acid metabolism and gut microbiota metabolism, were identified. Puerarin could prevent blood stasis through partially regulating the disturbed metabolic pathways. This work highlights that metabonomics is a valuable tool for studying the essence of blood stasis as well as evaluating the efficacy of the corresponding drug treatment.     

Role of platelet-activating factor in renal function in normal rats and rats with bilateral ureteral obstruction

Platelet-activating factor (PAF) is a powerful vasodilator with important effects on kidney function. It has been suggested that the renal effects of PAF are mediated by thromboxane A2 (TxA2). We examined the effect of PAF on renal function in sham-operated rats and rats that had undergone unilateral release of bilateral ureteral obstruction (BUO) of 24-hr duration, a condition in which the synthesis of TxA2 is increased. To eliminate systemic hemodynamic changes, PAF was infused directly into the left renal artery using the lowest dose that affected renal function (2.3 x 10(-13) moles/min). Infusion of PAF significantly decreased the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in normal rats and rats with BUO. Normal (sham-operated) rats pretreated with an inhibitor of TxA2 synthesis also had a significant decrease in GFR after administration of PAF (ERPF also decreased, but not significantly). Rats with BUO pretreated with an inhibitor of TxA2 synthesis had significantly greater basal GFR and ERPF (increases of 72 and 171%, respectively) than untreated BUO rats. Administration of PAF to the former group further increased GFR and ERPF (by 37 and 39%, respectively; P less than 0.001). The role of endogenous PAF was evaluated by administering a specific PAF receptor antagonist. Sham-operated rats pretreated with high doses of the PAF receptor antagonist had significantly higher mean arterial pressure values than normal untreated rats, and had no decrease in GFR and ERPF during PAF infusion. Rats with BUO pretreated with the PAF antagonist had a significant, dose-dependent decrease in basal GFR and ERPF. These data suggest that endogenous PAF has a vasodilatory role in obstructive nephropathy. No significant differences in eicosanoid excretion in the urine corrected per GFR were observed during infusion of PAF in any of the groups examined. In BUO rats with intact TxA2 synthesis, exogenous administration of PAF decreased renal function, presumably through further increases in the production of TxA2. However, when TxA2 production was inhibited, PAF administration increased GFR and ERPF, presumably due to its unopposed vasodilatory properties. The data suggest an important role of PAF in the hemodynamic changes seen in obstructive nephropathy.     

SAMP1/Sku as a murine model for tubulointerstitial nephritis: a study using unilateral ureteral obstruction.

The SAMP1/Sku mouse is a substrain of the SAMP1 (senescence-accelerated-mouse prone 1) which exhibits renal mononuclear cell infiltration from a younger age. We hypothesized that this renal characteristic is related to the incidence of tubulointerstitial nephritis (TIN). The purpose of the present study was to evaluate the applicability of the SAMP1/Sku mouse as a murine model for TIN. TIN was experimentally induced by unilateral ureteral obstruction (UUO). The SAMP1/Sku and control ICR of both sexes received either a sham or UUO operation and were sacrificed 7 days after the operation. The kidneys of the mice were observed histopathologically, immunohistochemically and semiquantitatively. UUO kidneys showed mononuclear cell infiltration, tubular atrophy and interstitial fibrosis. In males, semiquantitative scores of mononuclear cell infiltration, tubular atrophy, and F4/80, alpha-smooth muscle actin (alpha-SMA) and transforming growth factor (TGF)-beta1 reactions were significantly higher in SAMP1/Sku than in ICR. Likewise, in females, tubular atrophy and F4/80 reaction scores were significantly higher in SAMP1/Sku than in ICR. In conclusion, induction of TIN damage by UUO was more serious in SAMP1/Sku mice than in ICR. Therefore, we propose that SAMP1/Sku mice, especially male SAMP1/Sku, have congenital risk factors for the development of TIN.