Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation

2007 ◽  
Vol 292 (4) ◽  
pp. F1141-F1150 ◽  
Author(s):  
Sakiko Ohga ◽  
Kenichi Shikata ◽  
Kosuke Yozai ◽  
Shinichi Okada ◽  
Daisuke Ogawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Diabetic Rats ◽  
Pyrrolidine Dithiocarbamate ◽  
Sprague Dawley ◽  
Diabetic Kidney ◽  
Ppar Γ ◽  
Glomerular Endothelial Cells ◽  
Anti Inflammatory ◽  
In The Diabetic Kidney

Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM+pio). Diabetes was induced by injection with streptozotocin (STZ). The DM+pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-β, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-κB activity was increased in diabetic rats and reduced by pioglitazone. PPAR-γ was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-κB in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-κB. However, pioglitazone did not show the changes in the presence of PPAR-γ antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-κB activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.

scholarly journals Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney

2001 ◽  
Vol 170 (3) ◽  
pp. 647-651 ◽  
Author(s):  
C Hill ◽  
A Flyvbjerg ◽  
R Rasch ◽  
M Bak ◽  
A Logan
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Western Blotting ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Human Monoclonal Antibody ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Diabetic Kidney ◽  
In The Diabetic Kidney

Diabetic nephropathy is characterised by an increase in glomerular and tubular fibrosis that compromises kidney function. The transforming growth factor-betas (TGF-betas) have been shown to play a major role in fibrosis and we have shown that TGF-beta2, in particular, increases co-ordinately with fibrogenesis in the diabetic kidney. The aim of this study was to investigate the changes in expression of extracellular matrix molecules in the diabetic kidney, with and without systemic administration of a recombinant human monoclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were split into two groups. The first were treated with 5 mg/kg irrelevant control IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recombinant monoclonal anti-TGF-beta2 IgG4 (termed CAT-152) systemically every second day for 14 days. A further group of six non-diabetic rats was also used as a control. Various biological parameters were measured daily throughout the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-propeptide, which is an indicator of the rate of collagen-I synthesis within the kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urinary albumin excretion (UAE) and kidney weights were all significantly higher than in the non-diabetic group (P<0.05, n=24, by ANOVA). In the anti-TGF-beta2-treated diabetic rats, kidney weights and UAE levels were decreased when compared with those in placebo-treated diabetics. Western blotting for the procollagen-I C-propeptide in kidney cortices showed a significant increase in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibrogenesis. By contrast, in anti-TGF-beta2-treated diabetic rats, levels of the propeptide remained at non-diabetic levels. In summary, a significant suppression of kidney fibrosis was seen in anti-TGF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats. We conclude that systemic delivery of CAT-152, a neutralising anti-TGF-beta2 antibody, during the acute stages of diabetic nephropathy reduces the rate of pathogenic fibrosis in the kidney.

Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats

2015 ◽  
Vol 309 (3) ◽  
pp. F227-F234 ◽  
Author(s):  
Julie O'Neill ◽  
Angelica Fasching ◽  
Liselotte Pihl ◽  
Daniela Patinha ◽  
Stephanie Franzén ◽  
...  
Keyword(s):  
Renal Cortex ◽  
Early Stage ◽  
Rat Kidney ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Diabetic Kidney ◽  
Excretory Function ◽  
In The Diabetic Kidney

Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na+-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na+ transport efficiency [tubular Na+ transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary Po2 in both control and diabetic kidneys during the inhibition of proximal Na+ reabsorption suggests the redistribution of active Na+ transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

scholarly journals Cigarette smoke inhalation aggravates diabetic kidney injury in rats

2019 ◽  
Vol 8 (6) ◽  
pp. 964-971 ◽  
Author(s):  
Songling Jiang ◽  
Do Van Quan ◽  
Jae Hyuck Sung ◽  
Moo-Yeol Lee ◽  
Hunjoo Ha
Keyword(s):  
Kidney Disease ◽  
Cigarette Smoke ◽  
Density Lipoprotein ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Smoke Inhalation ◽  
Lipoprotein Cholesterol ◽  
Sprague Dawley ◽  
Experimental Conditions ◽  
Diabetic Kidney

Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Epidemiological studies have demonstrated that cigarette smoke or nicotine is a risk factor for the progression of chronic kidney injury. The present study analyzed the kidney toxicity of cigarette smoke in experimental rats with DKD. Experimental diabetes was induced in 7-week-old Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin (60 mg kg−1). Four weeks after the induction of diabetes, rats were exposed to cigarette smoke (200 μg L−1), 4 h daily, and 5 days per week for 4 weeks. Cigarette smoke did not affect the levels of plasma glucose, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol or non-esterified fatty acids in both control and diabetic rats under the experimental conditions. Cigarette smoke, however, significantly increased diabetes-induced glomerular hypertrophy and urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion, suggesting exacerbation of diabetic kidney injury. Cigarette smoke promoted macrophage infiltration and fibrosis in the diabetic kidney. As expected, cigarette smoke increased oxidative stress in both control and diabetic rats. These data demonstrated that four weeks of exposure to cigarette smoke aggravated the progression of DKD in rats.

scholarly journals Early Enhanced Leucine-Rich α-2-Glycoprotein-1 Expression in Glomerular Endothelial Cells of Type 2 Diabetic Nephropathy Model Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Sona haku ◽  
Hiromichi Wakui ◽  
Kengo Azushima ◽  
Kotaro Haruhara ◽  
Sho Kinguchi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Endothelial Cell Proliferation ◽  
Glomerular Hypertrophy ◽  
Vegf Expression ◽  
Initial Development ◽  
Glomerular Endothelial Cells

Abnormal angiogenesis plays a major role in the development of early stage diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a classical proangiogenic factor that regulates abnormal glomerular angiogenesis linked to glomerular hypertrophy in the early stage of diabetic nephropathy. Leucine-rich α-2-glycoprotein-1 (LRG1) was recently reported as a novel proangiogenic factor that is expressed in endothelial cells and promotes angiogenesis by modulating the transforming growth factor-β signaling pathway. However, the pathophysiology of LRG1 in diabetic nephropathy remains largely unknown. In the present study, we investigated intrarenal expression of the novel proangiogenic factor LRG1 in diabetic db/db mice by immunohistochemistry and a laser capture microdissection method during the development of diabetic nephropathy. We hypothesized that glomerular LRG1 expression is increased earlier than VEGF expression under conditions of pathological angiogenesis in the early stage of diabetic nephropathy. Thus, we compared glomerular expression of VEGF and LRG1 in diabetic db/db mice at 16 and 24 weeks of age. At 16 weeks, diabetic db/db mice exhibited glomerular hypertrophy with abnormal angiogenesis characterized by endothelial cell proliferation, which was concomitant with an increase in LRG1 expression of glomerular endothelial cells. However, glomerular VEGF expression was not increased at this early stage. At 24 weeks, the features of early diabetic nephropathy in db/db mice had developed further, along with further enhanced glomerular LRG1 expression. At this late stage, glomerular VEGF and fibrosis-related-gene expression was also significantly increased compared with nondiabetic db/m mice. These results suggest that LRG1 plays a pivotal role in the initial development of diabetic nephropathy by promoting abnormal angiogenesis, thereby suggesting that LRG1 is a potential preemptive therapeutic target of diabetic nephropathy.

Traditional drink of black cincau (Mesona palustris BL)-based wedang uwuh as immunomodulator on alloxan-induced diabetic rats

2020 ◽  
Vol 50 (6) ◽  
pp. 1123-1133
Author(s):  
Tri Dewanti Widyaningsih ◽  
Astri Iga Siska ◽  
Roudlatul Fanani ◽  
Erryana Martati
Keyword(s):  
Inflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Immunomodulatory Effect ◽  
Immunomodulatory Activity ◽  
Content Type ◽  
Anti Inflammatory ◽  
Red Ginger

Purpose This study aims to evaluate the immunomodulatory effect of traditional drink of black cincau-based wedang uwuh (WUB) on alloxan-induced diabetic rats. Design/methodology/approach WUB consists of dried herbs such as black cincau leaves (Mesona palustris BL), red ginger (Zingiber officinale Rosc), cloves (Syzgium aromaticum), sappan wood (Caesalpinia sappan Lin) and soursop leaves (Annona muricata). In this study, the rats were divided into five groups: normal control, diabetic control and three groups of WUB (WUB 13.5 mL/kg and WUB 27 mL/kg) or wedang uwuh commercial (WUC) treated diabetic groups. WUB or WUC was administered by gavage for three days after rats were confirmed diabetic induced by alloxan; these injections were continued for 28 days. At the end of the experiment, the spleen of rats was analyzed using flow cytometry. Data were analyzed by ANOVA followed by Tukey test using Minitab version 16.0. Findings This study showed that WUB significantly inhibited the expression of pro-inflammatory cytokines (interferon-Y [IFN-ɣ] and tumor necrosis factor-α [TNF-a]) and anti-inflammatory cytokines (interleukin 10 [IL-10] and transforming growth factor-β [TGF-ß]), and achieved a balance between pro-inflammatory and anti-inflammatory cytokines that were not significantly different from normal controls. WUB 27 was able to regulate the production of relative average cytokines IFN-ɣ (7.6 ± 3.5; p = 0.010), TNF-a (8.7 ± 2.4; p = 0.018), IL-10 (6.3 ± 2.4; p = 0.001) and TGF-ß (7.4 ± 2.1; p = 0.004) that was significantly different from diabetic control. This study’s results validate that the use of WUB can result in immunomodulatory activity in diabetic rats. Originality/value To the best of the authors’ knowledge, this is the first study on the immunomodulatory effect of WUB which is developed based on WUC; WUB has been used by Indonesian people as a functional beverage which acts as an immune booster and body warmer.

Regression of white adipose tissue in diabetic rats

1989 ◽  
Vol 257 (4) ◽  
pp. E547-E553 ◽  
Author(s):  
A. Geloen ◽  
P. E. Roy ◽  
L. J. Bukowiecki
Keyword(s):  
Endothelial Cells ◽  
Adipose Tissue ◽  
Protein Content ◽  
Cell Number ◽  
Diabetic Rats ◽  
Total Protein Content ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Wet Weight

The effects of long-term diabetes (4 wk) on the development of parametrial (PWAT) and retroperitoneal (RWAT) white adipose tissues were studied in young Sprague-Dawley rats (170-200 g) injected with a single dose of streptozotocin (75 mg/kg). Diabetes stopped animal growth and totally abolished the normal increases in the wet weight, total protein content, and cellularity (estimated by DNA content) of PWAT and RWAT. Remarkably, the prolonged lack of insulin induced a progressive decrease of the cellularity of RWAT to levels that were lower than those of the initial controls. It also resulted in a marked reduction of adipocyte size. The tiny adipocytes seen in diabetic animals were characterized by the presence of multilocular triglyceride droplets. In general, the decreases in cell number, cell size, and protein content were more pronounced in RWAT than in PWAT. Quantitative cellular frequency studies revealed that adipocytes, and possibly also endothelial cells, contribute to the decrease in RWAT cellularity. The results demonstrate that 1) diabetes inhibits proliferative activity in adipose tissue, 2) total cell number reduction may occur in adipose depot of young growing rats, 3) this effect is depot dependent, and 4) the turnover of adipocytes and endothelial cells is relatively slow (several weeks).

scholarly journals Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats

2010 ◽  
Vol 118 (3) ◽  
pp. 211-220 ◽  
Author(s):  
Giovanna Castoldi ◽  
Cira R. T. Di Gioia ◽  
Camila Bombardi ◽  
Carla Perego ◽  
Lucia Perego ◽  
...  
Keyword(s):  
Diastolic Function ◽  
Diabetic Cardiomyopathy ◽  
Transforming Growth Factor ◽  
Systolic Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Doppler Velocity ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Tgf Β1

Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is a physiological tetrapeptide hydrolysed by ACE (angiotensin-converting enzyme). In experimental models of hypertension, Ac-SDKP has antifibrotic effects in the heart; however, the role of Ac-SDKP in diabetic cardiomyopathy is currently unknown. The aim of the present study was to evaluate the effect of Ac-SDKP on cardiac systolic and diastolic function, and interstitial and perivascular fibrosis in the heart of diabetic rats. Diabetes was induced in 55 Sprague–Dawley rats by streptozotocin injection. Control rats (n=18) underwent only buffer injection. Out of the 55 diabetic rats, 19 were chronically treated with insulin and 13 with the ACEI (ACE inhibitor) ramipril (3 mg·kg−1 of body weight·day−1). At 2 months after the onset of diabetes, Ac-SDKP (1 mg·kg−1 of body weight·day−1) was administered by osmotic minipumps for 8 weeks to eight control rats, 13 diabetic rats, seven diabetic rats treated with ramipril and nine insulin-treated diabetic rats. Diabetic rats had a significant increase in blood glucose levels. Left ventricular interstitial and perivascular fibrosis, and TGF-β1 (transforming growth factor-β1) protein levels were increased in diabetic rats, but not in insulin-treated diabetic rats and ramipril-treated diabetic rats, compared with control rats. Ac-SDKP administration significantly reduced left ventricular interstitial and perivascular fibrosis in diabetic rats and in diabetic rats treated with ramipril. This was accompanied by a significant reduction in active TGF-β1 and phospho-Smad2/3 protein levels in myocardial tissue of diabetic rats. Echocardiography showed that diabetes was associated with increased end-systolic diameters, and depressed global systolic function and diastolic dysfunction, as assessed by transmitral Doppler velocity profile. These changes were completely reversed by insulin or ramipril treatment. Ac-SDKP treatment partially restored diastolic function in diabetic rats. In conclusion, Ac-SDKP administration in diabetic rats reduces left ventricular interstitial and perivascular fibrosis, active TGF-β1 and phospho-Smad2/3 levels, and improves diastolic function. Taken together, these findings suggest that, by inhibiting the TGF-β/Smad pathway, Ac-SDKP protects against the development of diabetic cardiomyopathy.

scholarly journals LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

2019 ◽  
Vol 30 (4) ◽  
pp. 546-562 ◽  
Author(s):  
Quan Hong ◽  
Lu Zhang ◽  
Jia Fu ◽  
Divya A. Verghese ◽  
Kinsuk Chauhan ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Renal Outcome ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Genetic Ablation ◽  
Glomerular Endothelial Cells

BackgroundGlomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-β/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear.MethodsWe analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.ResultsLRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.ConclusionsThese findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

scholarly journals Manganese exposure induces permeability in renal glomerular endothelial cells via the Smad2/3-Snail–VE-cadherin axis

2020 ◽  
Vol 9 (5) ◽  
pp. 683-692
Author(s):  
Peng Gao ◽  
Yutian Tian ◽  
Qi Xie ◽  
Liang Zhang ◽  
Yongjian Yan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Zinc Finger Protein ◽  
Vascular Endothelial ◽  
Sprague Dawley ◽  
Glomerular Diseases ◽  
Cell Monolayers ◽  
Vascular Endothelial Cadherin ◽  
Glomerular Endothelial Cells ◽  
Sprague Dawley Rats ◽  
Glomerular Endothelium

Abstract Manganese (Mn) is an essential micronutrient. However, it is well established that Mn overexposure causes nervous system diseases. In contrast, there are few reports on the effects of Mn exposure on glomerular endothelium. In the present study, the potential effects of Mn exposure on glomerular endothelium were evaluated. Sprague Dawley rats were used as a model of Mn overexposure by intraperitoneal injection of MnCl2·H2O at 25 mg/kg body weight. Mn exposure decreased expression of vascular endothelial-cadherin, a key component of adherens junctions, and increased exudate from glomeruli in Sprague Dawley rats. Human renal glomerular endothelial cells were cultured with different concentration of Mn. Exposure to 0.2 mM Mn increased permeability of human renal glomerular endothelial cell monolayers and decreased vascular endothelial-cadherin expression without inducing cytotoxicity. In addition, Mn exposure increased phosphorylation of mothers against decapentaplegic homolog 2/3 and upregulated expression of zinc finger protein SNAI1, a negative transcriptional regulator of vascular endothelial-cadherin. Our data suggest Mn exposure may contribute to development of glomerular diseases by inducing permeability of glomerular endothelium.

scholarly journals P0719SRC KINASES AGGRAVATE DIABETIC KIDNEY INJURY THROUGH ACTIVATION OF ENDOPLASMIC RETICULUM STRESS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Debra Dorotea ◽  
Hunjoo Ha
Keyword(s):  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Src Kinases ◽  
Mrna Levels ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
In The Diabetic Kidney

Abstract Background and Aims Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease which is characterized by prominent kidney fibrosis. Src family kinases (SFKs), a family of proto-oncogenes, has been acknowledged to mediate the development of kidney fibrosis. While, several studies in liver and skeletal muscle suggested the role of Src kinases in activating endoplasmic reticulum (ER) stress. The present study aimed to investigate the mechanism of Src kinases-ER stress in mediating the progression of DKD. Method Type 1 diabetes was induced by a single 60 mg/kg i.p injection of streptozotocin (STZ) in 7-week-old male, Sprague-Dawley rats. Diabetic rats received 8-week-treatment of either KF-1607 (30 mg/kg/day), a pharmacological inhibitor of SFKs, or losartan (1 mg/kg/day), a standard treatment for patients with DKD. Results Among SFKs, Fyn and Lyn kinases were particularly increased in the diabetic kidney. Inhibition of Src kinases by KF-1607 improved kidney function and inhibited tubular injury, presented by decreased serum creatinine, albuminuria, and urinary KIM-1 excretion. Pathological changes in the kidney, such as enhanced glomerular volume, tuft area, and fractional mesangial area, were ameliorated in KF-treated rats. Highly-accumulated collagen network as well as increased TGF-β and α-SMA mRNA levels in the diabetic kidney were also significantly reduced in response to KF treatment. Furthermore, it consistently attenuated kidney inflammation and oxidative stress. The renoprotective effects of KF were interestingly similar to those of losartan. We showed increases in protein levels of phosphorylated IRE-1α, ATF6, GRP78 as well as CHOP indicating an exacerbated ER stress in the diabetic kidney. These ER stress markers were significantly decreased in KF treated mice. Conclusion Altogether, Src kinases through activation of ER stress aggravates kidney injury in STZ-induced diabetic rats.

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