scholarly journals Sgk, a Putative Serine/Threonine Kinase, Is Differentially Expressed in the Kidney of Diabetic Mice and Humans

1999 ◽  
Vol 10 (12) ◽  
pp. 2488-2494
Author(s):  
JANET M. KUMAR ◽  
DAVID P. BROOKS ◽  
BARBARA A. OLSON ◽  
NICHOLAS J. LAPING
Keyword(s):  
Cell Culture ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Diabetic Mouse ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Serine Threonine Kinase ◽  
Differential Display Pcr ◽  
Threonine Kinase ◽  
Progression Of Renal Disease

Abstract. Differential display PCR was used to identify alternate expression of serum glucocorticoid-regulated kinase (Sgk) mRNA in diabetes-induced renal disease. Differential expression of Sgk mRNA was identified in the kidneys of normal and obese db/db mice, a model of select aspects of human diabetic nephropathy. Sgk mRNA was selectively increased in diabetic mouse kidneys. The Sgk mRNA levels remained constant in other tissues from obese db/db mice. An increase in Sgk mRNA was also observed in the human diabetic kidney. In addition, thrombin, which may play a role in the progression of renal disease, increased Sgk message in cell culture. Because the diabetes-induced increase in Sgk was only observed in the kidney, which is particularly susceptible to diabetes-induced damage, Sgk may play a role in diabetic nephropathy.

scholarly journals Induction of leukocyte adhesion molecules and renal physiologically active molecules in Porphyromonas gingivalis lipopolysaccharide-induced diabetic nephropathy

2020 ◽  
Author(s):  
Koichiro Kajiwara ◽  
Yoshihiko Sawa ◽  
Takahiro Fujita ◽  
Sachio Tamaoki
Keyword(s):  
Diabetic Nephropathy ◽  
Adhesion Molecules ◽  
Leukocyte Adhesion ◽  
Diabetic Mouse ◽  
Renal Parenchyma ◽  
Periodontal Pathogen ◽  
Diabetic Patients ◽  
Renal Tubules ◽  
Diabetic Mice ◽  
Leukocyte Adhesion Molecules

Abstract Background We recently reported that the glomerular endothelium expresses toll-like receptor (TLR)2 and TLR4 in diabetic environments and established that the TLR2 ligand Porphyromonas (P.) gingivalis lipopolysaccharides (LPS) induces nephropathy in diabetic mice. It is thought that P. gingivalis LPS promotes the chronic inflammation with the overexpression of leukocyte adhesion molecules and renal-specific metabolic enzymes by the recognition of P. gingivalis LPS via TLR in the diabetic kidneys. The present study aims to examine the expression of leukocyte adhesion molecules and renal metabolic factors in mouse kidneys with periodontal pathogen P. gingivalis LPS-induced diabetic nephropathy that was recently established. Methods The immunohistochemical investigation was performed on mouse kidney with P. gingivalis LPS-induced diabetic nephropathy model with glomerulosclerosis in glomeruli. Results There were no vessels which expressed vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or fibroblast growth factor (FGF) 23 in diabetic mice, or in healthy mice administered P. gingivalis LPS. However, in diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy the expression of VCAM-1 and the accumulation of FGF23 were established in renal tubules and glomeruli, and the expression of E-selectin was established in renal parenchyma and glomeruli. The angiotensin-converting enzyme 2 (ACE2) was detected in the proximal tubules but not in other regions including not in distal tubules of diabetic mice without LPS, and not in healthy mice administered P. gingivalis LPS. In diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy ACE2 was detected both in renal tubules as well as in glomeruli. The macrophage-1 (Mac-1) and podoplanin-positive cells increased in the renal parenchyma with diabetic condition and there was accumulation in P. gingivalis LPS-induced diabetic nephropathy. As the expression of VCAM-1 and E-selectin is upregulated in glomeruli, tubules, and intertubular capillaries, it is thought that the inflammatory infiltration of the monocyte-macrophage lineage promoted in kidneys with P. gingivalis LPS-induced the diabetic nephropathy. Conclusions P. gingivalis LPS may progressively accelerate the development of the renal inflammatory environment in LPS-accumulated glomeruli with the macrophage infiltration via the renal expression of VCAM-1 and E-selectin, and with ACE2 overexpression and FGF23 accumulation. Periodontitis may be a critical factor in the progress of nephropathy in diabetic patients.

Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy

2018 ◽  
Vol 52 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Sisse A Nørgaard ◽  
Fredrik W Sand ◽  
Dorte B Sørensen ◽  
Klas SP Abelson ◽  
Henrik Søndergaard
Keyword(s):  
Weight Loss ◽  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Diabetic Mouse ◽  
Diabetic Mice ◽  
Reduce Weight Loss ◽  
Normal Chow ◽  
Corticosterone Metabolites ◽  
Reducing Stress ◽  
Humane Endpoint

The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice without this supplement reached this humane endpoint ( p = 0.0027). Excretion of corticosterone metabolites in faeces was reduced in diabetic mice on softened chow ( p = 0.0007), suggesting lower levels of general stress. Finally, it was demonstrated that the water-softened chow supplement did not significantly affect the induction of key disease parameters, i.e. %HbA1C and albuminuria nor result in abnormal teeth wear. In conclusion, supplementation of softened food is refining the STZ-induced diabetic mouse model significantly by reducing stress, weight loss and the number of animals sacrificed due to humane endpoints, while maintaining the key phenotypes of diabetes and nephropathy.

scholarly journals Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis

2011 ◽  
Vol 300 (4) ◽  
pp. F873-F886 ◽  
Author(s):  
Daisuke Saito ◽  
Yohei Maeshima ◽  
Tatsuyo Nasu ◽  
Hiroko Yamasaki ◽  
Katsuyuki Tanabe ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Efficacy ◽  
Transforming Growth Factor ◽  
Angiogenesis Inhibitor ◽  
Therapeutic Effects ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Protein Levels ◽  
Type 2 Diabetic

The involvement of VEGF-A as well as the therapeutic efficacy of angiogenesis inhibitors in diabetic nephropathy have been reported. We recently reported the therapeutic effects of vasohibin-1 (VASH-1), an endogenous angiogenesis inhibitor, in a type 1 diabetic nephropathy model (Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Diabetes 58: 2365–2375, 2009). In this study, we investigated the therapeutic efficacy of VASH-1 on renal alterations in obese mice with type 2 diabetes. Diabetic db/db mice received intravenous injections of adenoviral vectors encoding human VASH-1 (AdhVASH-1) and were euthanized 8 wk later. AdhVASH-1 treatment resulted in significant suppression of glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase in the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix. An increase in the renal levels of VEGF-A, VEGFR-2, transforming growth factor (TGF)-β1, and monocyte chemoattractant protein-1 in diabetic animals was significantly suppressed by AdhVASH-1 (immunoblotting). AdhVASH-1 treatment significantly recovered the loss and altered the distribution patterns of nephrin and zonula occludens (ZO)-1 and suppressed the increase in the number of fibroblast-specific protein-1 (FSP-1+) and desmin+ podocytes in diabetic mice. In vitro, recombinant human VASH-1 (rhVASH-1) dose dependently suppressed the upregulation of VEGF induced by high ambient glucose (25 mM) in cultured mouse podocytes. In addition, rhVASH-1 significantly recovered the mRNA levels of nephrin and the protein levels of ZO-1 and P-cadherin and suppressed the increase in protein levels of desmin, FSP-1, Snail, and Slug in podocytes under high-glucose condition. Taken together, these results suggest the potential use of VASH-1 as a novel therapeutic agent in type 2 diabetic nephropathy mediated via antiangiogenic effects and maintenance of podocyte phenotype in association with antiproteinuric effects.

Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice

2010 ◽  
Vol 298 (3) ◽  
pp. F609-F616 ◽  
Author(s):  
Tomoki Kosugi ◽  
Takahiro Nakayama ◽  
Qiuhong Li ◽  
Vince A. Chiodo ◽  
Li Zhang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Diabetic Nephropathy ◽  
Diabetic Mice ◽  
Tubulointerstitial Injury ◽  
Podocyte Injury ◽  
Adeno Associated Virus ◽  
Translational Study ◽  
Renal Histology ◽  
Progression Of Renal Disease ◽  
Different Doses

VEGF is recognized as a major mediator in the development of diabetic nephropathy. Soluble Flt-1 (sFlt-1) is the endogenous inhibitor of VEGF, and recently genetic overexpression of sFlt-1 in the podocyte was shown to be protective in murine diabetic nephropathy. In this study, we performed a translational study to determine whether an intramuscular gene transfer of sFlt-1 can prevent the progression of renal disease in diabetic db/db mice. Adeno-associated virus-1 (AAV1) encoding human sFlt-1 in two different doses was intramuscularly administrated in db/db and wild-type mice. The sFlt-1-AAV1 treatment significantly increased serum sFlt-1 level at 4 and 8 wk. A dose that was developed in this study caused minimal abnormalities in normal mice but reduced albuminuria in diabetic db/db mice. In renal histology, sFlt-1 treatment at this dose had minimal effects on mesangial expansion in diabetic mice, whereas podocyte injury was significantly improved, at 8 wk. Unfortunately, tubulointerstitial injury was markedly exacerbated by sFlt-1 treatment in association with a reduction in endogenous VEGF expression and peritubular capillary loss. In conclusion, gene therapy with sFlt-1-AAV1 protects podocytes but accelerates tubulointerstitial injury in diabetic db/db mice. These data suggest systemic overexpression of sFlt-1 will not likely be useful for treating diabetic nephropathy.

scholarly journals Maslinic Acid Activates Renal Ampk/sirt1 Signaling Pathway to Protect Against Diabetic Nephropathy in Mice

2021 ◽  
Author(s):  
Huijuan Gao ◽  
Hong Wu
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Acid Treatment ◽  
Diabetic Mouse ◽  
Diabetic Mice ◽  
Pentacyclic Triterpene ◽  
Triterpene Acid ◽  
Maslinic Acid

Abstract BackgroundDiabetic nephropathy has been a devastating complication. Clinically, there is an urgent need for nephroprotective agents to delay the onset of diabetic nephropathy and ameliorate its symptoms. Maslinic acid is a pentacyclic triterpene acid with protective effect on multiple organs from oxidative stress and inflammation. However, the therapeutic effect of maslinic acid on diabetic nephropathy remains unclear.MethodsC57BL/6J male mice administrated with 50 mg/kg of Streptozocin (STZ) daily were used to establish diabetic mouse model (blood glucose levels > 300 mg/dL). Urinary levels of albumin, total proteins, and creatinine were analyzed by an automatic analyzer. H&E staining was used to evaluate renal damage. qRT-PCR and ELISA assay were performed to investigate the inflammation and oxidative stress of renal tissues. Western-blotting assay was used to demonstrate the activation of AMPK signaling.ResultsMaslinic acid treatment alleviated the loss of body weight and blood glucose in diabetic mice. The renal structure and function were protected by maslinic acid in diabetic mice. 20 mg/kg maslinic acid treatment for 8 weeks alleviated the oxidative stress and inflammation in the kidney of diabetic rats dramatically. Maslinic acid treatment activated renal AMPK/SIRT1 signaling.ConclusionMaslinic acid ameliorated diabetic nephropathy via activating AMPK/SIRT1 signaling pathway.

scholarly journals Involvement of p300/CBP and epigenetic histone acetylation in TGF-β1-mediated gene transcription in mesangial cells

2013 ◽  
Vol 304 (5) ◽  
pp. F601-F613 ◽  
Author(s):  
Hang Yuan ◽  
Marpadga A. Reddy ◽  
Guangdong Sun ◽  
Linda Lanting ◽  
Mei Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Histone Acetylation ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Mrna Levels ◽  
Creb Binding Protein ◽  
Diabetic Mice ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tgf Β1 ◽  
Pai 1

Transforming growth factor-β1 (TGF-β1)-induced expression of plasminogen activator inhibitor-1 (PAI-1) and p21 in renal mesangial cells (MCs) plays a major role in glomerulosclerosis and hypertrophy, key events in the pathogenesis of diabetic nephropathy. However, the involvement of histone acetyl transferases (HATs) and histone deacetylases (HDACs) that regulate epigenetic histone lysine acetylation, and their interaction with TGF-β1-responsive transcription factors, are not clear. We evaluated the roles of histone acetylation, specific HATs, and HDACs in TGF-β1-induced gene expression in rat mesangial cells (RMCs) and in glomeruli from diabetic mice. Overexpression of HATs CREB binding protein (CBP) or p300, but not p300/CBP-activating factor, significantly enhanced TGF-β1-induced PAI-1 and p21 mRNA levels as well as transactivation of their promoters in RMCs. Conversely, they were significantly attenuated by HAT domain mutants of CBP and p300 or overexpression of HDAC-1 and HDAC-5. Chromatin immunoprecipitation assays showed that TGF-β1 treatment led to a time-dependent enrichment of histone H3-lysine9/14-acetylation (H3K9/14Ac) and p300/CBP occupancies around Smad and Sp1 binding sites at the PAI-1 and p21 promoters. TGF-β1 also enhanced the interaction of p300 with Smad2/3 and Sp1 and increased Smad2/3 acetylation. High glucose-treated RMCs exhibited increased PAI-1 and p21 levels, and promoter H3K9/14Ac, which were blocked by TGF-β1 antibodies. Furthermore, increased PAI-1 and p21 expression was associated with elevated promoter H3K9/14Ac levels in glomeruli from diabetic mice. Thus TGF-β1-induced PAI-1 and p21 expression involves interaction of p300/CBP with Smads and Sp1, and increased promoter access via p300/CBP-induced H3K9/14Ac. This in turn can augment glomerular dysfunction linked to diabetic nephropathy.

scholarly journals Distinct roles of arginases 1 and 2 in diabetic nephropathy

2017 ◽  
Vol 313 (4) ◽  
pp. F899-F905 ◽  
Author(s):  
Sidney M. Morris ◽  
Hanning You ◽  
Ting Gao ◽  
Jean Vacher ◽  
Timothy K. Cooper ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Albumin Excretion Rate ◽  
Selective Inhibition ◽  
Diabetic Mouse ◽  
Macrophage Infiltration ◽  
Mrna Levels ◽  
Plasma Urea ◽  
Economic Productivity ◽  
Arginase 1

Diabetes is the leading cause of end-stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. Because current therapies for progression of diabetic nephropathy (DN) are only moderately successful, identification of underlying mechanisms of disease is essential to develop more effective therapies. We showed previously that inhibition of arginase using S-(2-boronoethyl)-l-cysteine (BEC) or genetic deficiency of the arginase-2 isozyme was protective against key features of nephropathy in diabetic mouse models. However, those studies did not determine whether all markers of DN were dependent only on arginase-2 expression. The objective of this study was to identify features of DN that are associated specifically with expression of arginase-1 or −2. Elevated urinary albumin excretion rate and plasma urea levels, increases in renal fibronectin mRNA levels, and decreased renal medullary blood flow were associated almost completely and specifically with arginase-2 expression, indicating that arginase-2 selectively mediates major aspects of diabetic renal injury. However, increases in renal macrophage infiltration and renal TNF-α mRNA levels occurred independent of arginase-2 expression but were almost entirely abolished by treatment with BEC, indicating a distinct role for arginase-1. We therefore generated mice with a macrophage-specific deletion of arginase-1 ( CD11bCre/ Arg1fl/fl). CD11bCre/ Arg1fl/fl mice had significantly reduced macrophage infiltration but had no effect on albuminuria compared with Arg1fl/fl mice after 12 wk of streptozotocin-induced diabetes. These results indicate that selective inhibition of arginase-2 would be effective in preventing or ameliorating major features of diabetic renal injury.

Low-protein diet and progression of renal disease in diabetic nephropathy

The Lancet ◽  
1990 ◽  
Vol 335 (8688) ◽  
pp. 550-551 ◽  
Author(s):  
Gian Carlo Viberti ◽  
James Walker ◽  
Rosemary Dodds
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Low Protein ◽  
Progression Of Renal Disease

Low-protein diet and progression of renal disease in diabetic nephropathy

The Lancet ◽  
1990 ◽  
Vol 335 (8686) ◽  
pp. 411-412 ◽  
Author(s):  
HansHenrik Parving ◽  
Masayoshi Shichiri ◽  
Yasuhide Nishio ◽  
Fumiaki Marumo
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Low Protein ◽  
Progression Of Renal Disease

scholarly journals Prevention of the progression of renal injury in diabetic rodent models with preexisting renal disease with chronic endothelin A receptor blockade

2018 ◽  
Vol 315 (4) ◽  
pp. F977-F985 ◽  
Author(s):  
Denisha Spires ◽  
Bibek Poudel ◽  
Corbin A. Shields ◽  
Alyssa Pennington ◽  
Brianca Fizer ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Arterial Pressure ◽  
Renal Disease ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Receptor Blockade ◽  
Glomerular Injury ◽  
Endothelin A ◽  
Renal Vascular ◽  
Progression Of Renal Disease

The endothelin (ET) system has emerged as a therapeutic target for the treatment of diabetic nephropathy (DN). The present study examined whether chronic endothelin A (ETA) receptor blockade with atrasentan prevents the progression of renal injury in two models of DN with preexisting renal disease that exhibit an increased renal ET-1 system compared with nondiabetic rats: streptozotocin-treated Dahl salt-sensitive (STZ-SS) and type 2 diabetic nephropathy (T2DN) rats. Nine week-old SS rats were treated with (STZ; 50 mg/kg ip) to induce diabetes. After 3 wk of diabetes, proteinuria increased to 353 ± 34 mg/day. The rats were then separated into two groups: 1) vehicle and 2) atrasentan (5 mg·kg−1·day−1) via drinking water. After 6 wk of treatment with atrasentan, mean arterial pressure (MAP) and proteinuria decreased by 12 and 40%, respectively, in STZ-SS rats. The degree of glomerulosclerosis and renal fibrosis was significantly reduced in the kidneys of atrasentan-treated STZ-SS rats compared with vehicle STZ-SS rats. Interestingly, treatment with atrasentan did not affect GFR but significantly increased renal blood flow by 33% and prevented the elevations in filtration fraction and renal vascular resistance by 23 and 20%, respectively, in STZ-SS rats. In contrast to the STZ-SS study, atrasentan had no effect on MAP or proteinuria in T2DN rats. However, treatment with atrasentan significantly decreased glomerular injury and renal fibrosis and prevented the decline in renal function in T2DN rats. These data indicate that chronic ETA blockade produces advantageous changes in renal hemodynamics that slow the progression of renal disease and also reduces renal histopathology in the absence of reducing arterial pressure and proteinuria.

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