Osteopontin Plays a Critical Role in Interstitial Fibrosis but Not Glomerular Sclerosis in Diabetic Nephropathy

Abstract Following our reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN)(25,34) we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulo-interstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerge from two defects: First, an increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium. Second, a defect of glomerular vessels consisting of an increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of the accumulated worn-out GBM-material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally healthy podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulo-tubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myo-fibroblasts resulting in interstitial fibrosis.

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Abstract 514: Jak2 Tyrosine Kinase Mediates Angiotensin II Renal Pathogenesis via its Pressor Dependent Actions

Hypertension ◽

10.1161/hyp.64.suppl_1.514 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Peter P Sayeski ◽

Sung O Park ◽

Annet Kirabo ◽

Rebekah Baskin ◽

Dale M Seth ◽

...

Keyword(s):

Angiotensin Ii ◽

Renal Injury ◽

Interstitial Fibrosis ◽

Critical Role ◽

Glomerular Sclerosis ◽

Control Group ◽

Mrna Levels ◽

Ang Ii ◽

Urine Albumin ◽

Independent Events

We previously found that Jak2 kinase, expressed within vascular smooth muscle cells (VSMC), plays a critical role in angiotensin II (Ang II)-mediated hypertension. Given that Jak2 mediates both pressor-dependent and pressor-independent events, we sought to determine the role of blood pressure (BP), per se, on the deleterious effects of Jak2 within the kidney. To investigate this, three groups of mice were examined; i) wild type mice (Controls) that received Ang II infusion, ii) mice lacking Jak2 expression within the VSMC (VSMC Jak2 Null) that also received Ang II, and iii) Control mice that received Ang II plus an anti-hypertensive triple therapy (3Rx). After baseline BP recordings, Ang II was infused (1000 ng/kg/min, SC) to all groups and the 3Rx regimen (80 mg/L hydralazine, 5 mg/L reserpine, 30 mg/L hydrochlorothiazide in the drinking water) was initiated two days later to the 3Rx group, in order to maintain BP at similar levels to the VSMC Jak2 Null group. After 28 days of Ang II, mice were euthanized and the kidneys were assessed via histological, molecular, and functional approaches. Chronic Ang II infusion significantly increased the levels of intrarenal Ang II in all three groups; Control = 1,262±283 fmol/g, VSMC Jak2 Null = 1,655±666 fmol/g, and 3Rx = 2,174±588. While Ang II infusion significantly increased the mean BP in the Control group (152 ± 2 mm Hg), it was significantly, and similarly, lower in both the VSMC Jak2 Null and 3Rx groups (125 ± 5 mm Hg and 131 ± 5 mm Hg, respectively). Glomerular sclerosis was absent and interstitial fibrosis ranged from absent- mild- moderate, and was similar in all groups. The increases in i) perivascular infiltration of CD3+ lymphocytes, ii) CTGF gene expression, iii) tubule casts and iv) albuminuria that were observed in the Control mice, were significantly reduced in both the VSMC Jak2 Null and 3Rx groups. [CTGF mRNA Levels: Control = 100%±17, VSMC Jak2 Null = 70%±12*, 3Rx= 56%±17*. Urine Albumin (ng/day): Control = 414 ± 262, VSMC Jak2 Null = 138 ± 172*, 3Rx= 101 ± 89* (*, p<0.05 vs. Control)]. Thus, the early renal injury due to chronic Ang II infusion correlates with increased BP and not with the expression of VSMC-derived Jak2, suggesting that Jak2 contributes to early Ang II-mediated renal injury via its pressor-dependent actions.

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Increased urinary miR-196a level predicts the progression of renal injury in patients with diabetic nephropathy

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy326 ◽

2018 ◽

Vol 35 (6) ◽

pp. 1009-1016 ◽

Cited By ~ 1

Author(s):

Yu An ◽

Changming Zhang ◽

Feng Xu ◽

Wei Li ◽

Caihong Zeng ◽

...

Keyword(s):

Diabetes Mellitus ◽

Diabetic Nephropathy ◽

Renal Injury ◽

Cox Regression ◽

Interstitial Fibrosis ◽

Glomerular Sclerosis ◽

Tubular Atrophy ◽

Cox Regression Analysis ◽

Stage Renal Disease ◽

End Stage

Abstract Background Recent data suggest that miR-196a is predominantly expressed in the kidney and plays an inhibitory role in the progress of renal interstitial fibrosis (IF). However, the predictive value of miR-196a in diabetic nephropathy (DN) remains unknown. We validated the role of urinary miR-196a in the progression of renal injury in a cohort of patients with type 2 diabetes mellitus. Methods Our study included 209 patients with biopsy-proven DN. The mean follow-up time was 54.03 ± 32.94 months. Histological lesions were assessed using the pathological classification established by the Renal Pathology Society. Percentages of IF and tubular atrophy were assessed using the Aperio ScanScope system. We measured the correlation of urinary miR-196a with clinical and pathological parameters using the Spearman’s correlation test. The influence of urinary miR-196a on renal outcomes was assessed using Cox regression analysis. Results Urinary miR-196a levels correlated positively with proteinuria (ρ = 0.385, P < 0.001), duration of diabetes mellitus (ρ = 0.255, P < 0.001) and systolic blood pressure (ρ = 0.267, P < 0.001). The baseline estimated glomerular filtration rate (eGFR) and hemoglobin level showed a negative correlation with urinary miR-196a (ρ = −0.247, P < 0.001 and ρ = −0.236, P = 0.001, respectively). Pathologically, urinary miR-196a levels correlated with glomerular sclerosis and IF in patients with DN. Urinary miR-196a was significantly associated with progression to end-stage renal disease [hazard ratio (HR) 2.03, P < 0.001] and a 40% reduction of baseline eGFR (HR 1.75, P = 0.001), independent of age, gender, body mass index, mean arterial pressure and hemoglobinA1c level. However, urinary miR-196a did not improve predictive power to proteinuria and eGFR in DN patients. Conclusions Increased urinary miR-196a was significantly associated with the progression of renal injury and might be a noninvasive prognostic marker of renal fibrosis in DN patients.

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IL-17 deficiency aggravates the streptozotocin‐induced diabetic nephropathy through the reduction of autophagosome formation in mice

Molecular Medicine ◽

10.1186/s10020-021-00285-4 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Kyung-Hyun Kim ◽

Geum-Lan Hong ◽

Da-Young Jung ◽

Shanika Karunasagara ◽

Won-Il Jeong ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Renal Damage ◽

Interstitial Fibrosis ◽

Critical Role ◽

Wild Type ◽

Autophagosome Formation ◽

Renal Interstitial Fibrosis ◽

Potential Therapeutic Target ◽

Important Mediator ◽

Associated Proteins

Abstract Background Diabetic nephropathy (DN) is one of the most important medical complications of diabetes mellitus. Autophagy is an important mediator of pathological response and plays a critical role in inflammation during the progression of diabetic nephropathy. Interleukin (IL)-17A favorably modulates inflammatory disorders including DN. In this study, we examined whether IL-17A deficiency affected the autophagy process in the kidneys of mice with streptozotocin (STZ)-induced DN. Methods The autophagic response of IL-17A to STZ-induced nephrotoxicity was evaluated by analyzing STZ-induced functional and histological renal injury in IL-17A knockout (KO) mice. Results IL-17A KO STZ-treated mice developed more severe nephropathy than STZ-treated wild-type (WT) mice, with increased glomerular damage and renal interstitial fibrosis at 12 weeks. IL-17A deficiency also increased the up-regulation of proinflammatory cytokines and fibrotic gene expression after STZ treatment. Meanwhile, autophagy-associated proteins were induced in STZ-treated WT mice. However, IL-17A KO STZ-treated mice displayed a significant decrease in protein expression. Especially, the levels of LC3 and ATG7, which play crucial roles in autophagosome formation, were notably decreased in the IL-17A KO STZ-treated mice compared with their WT counterparts. Conclusions IL-17 deficiency aggravates of STZ-induced DN via attenuation of autophagic response. Our study demonstrated that IL-17A mediates STZ-induced renal damage and represents a potential therapeutic target in DN.

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Bioinformatic Evaluation of Transcriptional Regulation of WNT Pathway Genes with reference to Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2016/7684038 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Gareth J. McKay ◽

David H. Kavanagh ◽

John K. Crean ◽

Alexander P. Maxwell

Keyword(s):

Transcription Factor ◽

Diabetic Nephropathy ◽

Wnt Pathway ◽

Interstitial Fibrosis ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Gene Promoter ◽

Therapeutic Benefit ◽

Fold Change ◽

Glomerular Sclerosis

Objective.WNT/β-catenin pathway members have been implicated in interstitial fibrosis and glomerular sclerosis disease processes characteristic of diabetic nephropathy (DN), processes partly controlled by transcription factors (TFs) that bind to gene promoter regions attenuating regulation. We sought to identify predictedcis-acting transcription factor binding sites (TFBSs) overrepresented within WNT pathway members.Methods.We assessed 62 TFBS motif frequencies from the JASPAR databases in 65 WNT pathway genes.Pvalues were estimated on the hypergeometric distribution for each TF. Gene expression profiles of enriched motifs were examined in DN-related datasets to assess clinical significance.Results.Transcription factor AP-2 alpha (TFAP2A), myeloid zinc finger 1 (MZF1), and specificity protein 1 (SP1) were significantly enriched within WNT pathway genes (Pvalues < 6.83 × 10−29, 1.34 × 10−11, and 3.01 × 10−6, resp.).MZF1expression was significantly increased in DN in a whole kidney dataset (fold change = 1.16; 16% increase;P=0.03).TFAP2Aexpression was decreased in an independent dataset (fold change = −1.02;P=0.03). No differential expression ofSP1was detected.Conclusions.Three TFBS profiles are significantly enriched within WNT pathway genes highlighting the potential ofin silicoanalyses for identification of pathway regulators. Modification of TF binding may possibly limit DN progression, offering potential therapeutic benefit.

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Multi-Omics Analysis of Diabetic Nephropathy Reveals Potential New Mechanisms and Drug Targets

Frontiers in Genetics ◽

10.3389/fgene.2020.616435 ◽

2020 ◽

Vol 11 ◽

Author(s):

Qian Sha ◽

Jinxiu Lyu ◽

Meng Zhao ◽

Haijuan Li ◽

Mengzhe Guo ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Drug Targets ◽

Molecular Mechanisms ◽

Interstitial Fibrosis ◽

Stearidonic Acid ◽

Fatty Acyl ◽

Glomerular Sclerosis ◽

Transporter Protein ◽

Stage Renal Disease

Diabetic nephropathy (DN) is one of the most common diabetic complications, which is the major course of end-stage renal disease (ESRD). However, the systematical molecular characterizations during DN pathogenesis and progression has not been not well understood. To identify the fundamental mediators of the pathogenesis and progression of DN. we performed a combination RNASeq, proteomics, and metabolomics analyses of both patients’ derived kidney biopsy samples and kidneys from in vivo DN model. As a result, molecular changes of DN contain extracellular matrix accumulation, abnormal activated inflamed microenvironment, and metabolism disorders, bringing about glomerular sclerosis and tubular interstitial fibrosis. Specificity, Further integration analyses have identified that the linoleic acid metabolism and fatty-acids β-oxidation are significantly inhibited during DN pathogenesis and progression, the transporter protein ABCD3, the fatty acyl-CoA activated enzymes ACOX1, ACOX2, and ACOX3, and some corresponding metabolites such as 13′-HODE, stearidonic acid, docosahexaenoic acid, (±)10(11)-EpDPA were also significantly reduced. Our study thus provides potential molecular mechanisms for DN progression and suggests that targeting the key enzymes or supplying some lipids may be a promising avenue in the treatment of DN, especially advanced-stage DN.

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Protective Effects of Chromium Picolinate Against Diabetic-Induced Renal Dysfunction and Renal Fibrosis in Streptozotocin-Induced Diabetic Rats

Biomolecules ◽

10.3390/biom10030398 ◽

2020 ◽

Vol 10 (3) ◽

pp. 398 ◽

Cited By ~ 3

Author(s):

Shan Shan Qi ◽

Hong Xing Zheng ◽

Hai Jiang ◽

Li Ping Yuan ◽

Le Chen Dong

Keyword(s):

Diabetic Nephropathy ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Biological Activities ◽

Serum Insulin ◽

Treated Group ◽

Chromium Picolinate ◽

Glomerular Sclerosis ◽

Protective Effects ◽

Tgf Β1

Diabetic nephropathy (DN) is one of the most important complications of diabetes, and the leading cause of end-stage renal disease (ESRD). While Chromium picolinate (CrPic) supplementation has been found to be effective in treating diabetes, its effects on diabetic-induced nephropathy have not been studied. Therefore, in this study, CrPic (1 mg kg−1 d−1) was administered to a DN rat model by oral gavage for eight weeks to investigate its effects. The results show that CrPic supplementation caused a decrease in levels of blood glucose, serum insulin, blood urea nitrogen (BUN), serum creatinine, and urinary albumin in DN rats. It also reversed renal pathological changes, including renal glomerular sclerosis and interstitial fibrosis. In addition, the oxidative defense system in the kidneys of DN rats was found to be improved; the biological activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) increased; and the content of malondialdehyde (MDA) lowered. Immunohistochemical results reveal that the expression levels of renal transforming growth factor-β1 (TGF-β1), Smad 2, and Smad 3 decreased significantly in the kidneys of rats in the CrPic-treated group. CrPic administration was thus found to ameliorate diabetic nephropathy in SD rats via an antioxidative stress mechanism, as well the ability to inhibit TGF-β1/Smad2/3 expression. This study suggests that CrPic could be a potential renal-protective nutrient against diabetic nephropathy.

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Protective Effects of Ethanolic Extract from Rhizome of Polygoni avicularis against Renal Fibrosis and Inflammation in a Diabetic Nephropathy Model

International Journal of Molecular Sciences ◽

10.3390/ijms22137230 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7230

Author(s):

Jung-Joo Yoon ◽

Ji-Hun Park ◽

Yun-Jung Lee ◽

Hye-Yoom Kim ◽

Byung-Hyuk Han ◽

...

Keyword(s):

Insulin Resistance ◽

Diabetic Nephropathy ◽

Renal Dysfunction ◽

Renal Fibrosis ◽

Mesangial Cells ◽

Resistance Index ◽

Ethanolic Extract ◽

Glomerular Sclerosis ◽

Oral Glucose ◽

Inflammatory Factor

Progressive diabetic nephropathy (DN) in diabetes leads to major morbidity and mortality. The major pathological alterations of DN include mesangial expansion, extracellular matrix alterations, tubulointerstitial fibrosis, and glomerular sclerosis. Polygoni avicularis is widely used in traditional oriental medicine and has long been used as a diuretic, astringent, insecticide and antihypertensive. However, to the best of the authors’ knowledge, the effects of the ethanolic extract from rhizome of Polygoni avicularis (ER-PA) on DN have not yet been assessed. The present study aimed to identify the effect of ER-PA on renal dysfunction, which has been implicated in DN in human renal mesangial cells and db/db mice and investigate its mechanism of action. The in vivo experiment was performed using Polygoni avicularis-ethanol soluble fraction (ER-PA) and was administrated to db/db mice at 10 and 50 mg/kg dose. For the in vitro experiments, the human renal mesangial cells were induced by high glucose (HG, 25 mM). The ER-PA group showed significant amelioration in oral glucose tolerance, and insulin resistance index. ER-PA significantly improved the albumin excretion and markedly reduced plasma creatinine, kidney injury molecule-1 and C-reactive protein. In addition, ER-PA significantly suppressed inflammatory cytokines. Histopathologically, ER-PA attenuated glomerular expansion and tubular fibrosis in db/db mice. Furthermore, ER-PA suppressed the expression of renal fibrosis biomarkers (TGF and Collagen IV). ER-PA also reduced the NLR family pyrin domain containing 3 inflammatory factor level. These results suggest that ER-PA has a protective effect against renal dysfunction through improved insulin resistance as well as the inhibition of nephritis and fibrosis in DN.

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LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

American Journal of Nephrology ◽

10.1159/000514167 ◽

2021 ◽

pp. 1-11

Author(s):

Ting-Ting Liu ◽

Ran Luo ◽

Yi Yang ◽

Yi-Chun Cheng ◽

Dan Chang ◽

...

Keyword(s):

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Critical Role ◽

Tube Formation ◽

Renal Interstitial Fibrosis ◽

Genetic Ablation ◽

Capillary Rarefaction ◽

Peritubular Capillaries ◽

Renal Tubular

Introduction: Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. Methods: We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. Results: We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-β1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. Conclusion: LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

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Moxibustion Alleviates Injury in a Rat Focal Segmental Glomerulosclerosis Model

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/7169547 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Yi Li ◽

Yuxia Sun ◽

Chunling Zhang ◽

Ke Wang ◽

Peicheng Shen ◽

...

Keyword(s):

Focal Segmental Glomerulosclerosis ◽

Rat Model ◽

Interstitial Fibrosis ◽

Similar Efficacy ◽

Glomerular Sclerosis ◽

Control Group ◽

Therapeutic Effects ◽

Repeated Injection ◽

Moxibustion Group ◽

Segmental Glomerulosclerosis

Objectives. To evaluate the therapeutic effects of moxibustion at Shenshu (BL-23) and Geshu (BL-17) acupoints in a focal segmental glomerulosclerosis (FSGS) model in rats. Methods. A FSGS rat model was established by single nephrectomy and repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, losartan (positive control) group, Shenshu moxibustion group, and Geshu moxibustion group. Molecular indicators of kidney function and renal pathological changes were monitored. Results. Urinary protein, serum creatinine, urea nitrogen, and serum uric acid were significantly reduced after 12-week intervention with losartan, Shenshu, or Geshu moxibustion. Renal α-SMA, FN, and TGF-β were also decreased, while podocin and nephrin protein and mRNA were increased. The pathological damage in renal tissue was obviously alleviated by all three treatments, which suggests that moxibustion may have similar efficacy to losartan in the treatment of FSGS. Conclusion. Moxibustion alleviates podocyte injury and inhibits renal interstitial fibrosis in the FSGS rat model, thereby minimizing the progression of glomerular sclerosis and improving renal function.

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