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KK-Ay mouse: Diabetic nephropathy model by Unilateral nephrectomy & Salt supplementation / Diet inducting (QF* and WD*)

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KK-Ay mouse: Diabetic nephropathy model by Unilateral nephrectomy & Salt supplementation / Diet inducting (QF* and WD*)

KK-Ay mouse is suitable as a diabetic nephropathy animal model by using two experimental methods.


We established two methods to make a diabetic nephropathy model for KK-Ay mice as below:

Table of contents:

Inducing method1: Unilateral nephrectomy (Nx) with salt supplementation  

Inducing method2: Diet induce (Hight fat diet QF and WD)

 

By the above 2 methods, diabetic nephropathy was established and expedited in KK-Ay mice.  KK-Ay mouse should be useful as a diabetic nephropathy animal model to evaluate basic and drug efficacy studies.

If you are interested, please feel free to contact us.

*QF: Quick Fat (QF) is a high-fat diet for diabetes and obesity research supplied by CLEA Japan, inc. →QF product page

*WD: Western Diet (WD) is a special diet containing 2% cholesterol added to QF.

Promotion:

Please refer to the below URL if you need to have more human resembled diabetic nephropathy animal model.  Our type 2 diabetic and obesity model, SDT fatty rat, could evaluate drug efficacy study more accuracy from hyperfiltration to glomerular filtration rate (GFR) decreasing nephropathy phase.

Development of diabetic nephropathy evaluation system using SDT fatty rats: control drug SGLT-2 inhibitor, ACE inhibitor, GLP-1 agonist

◆Inducing method 1: Nx and salt supplementation

Diabetic nephropathy was observed early in KK-Ay mice by executing unilateral Nx and salt supplementation. Hyperglycemia persisted after nephrectomy, gene expression and histopathological analysis confirmed renal complications.


Study design

These mice were divided into six groups.  Not only Nx but also with salt supplement groups were set and observed the effects by salt supplementation additionally.

  Name of group Animal Feed water
Group 1 Cont C57B6 CE-2 water
Group 2 Cont-Nx C57B6 CE-2 water
Group 3  Cont-Nx+NaCl  C57B6  CE-2  0.9%NaCl 
Group 4 KKAy KK-Ay CE-2 water
Group 5 KKAy-Nx KK-Ay CE-2 water
Group 6 KKAy-Nx+NaCl KK-Ay CE-2 0.9%NaCl


Study design

The 45th Japanese Society of Toxicology (2018)

Result

Diabetic symptoms were significantly expressed in all KK-Ay mouse groups. (Body weight, food and water intake, blood glucose level).

Result

The 45th Japanese Society of Toxicology (2018)

Kidney biopsy

Renal hypertrophy was confirmed in the KK-Ay-Nx and KK-Ay-Nx + NaCl groups.
Kidney biopsy

The 45th Japanese Society of Toxicology (2018)



Body Organ weight analysis

The 45th Japanese Society of Toxicology (2018)

Plasma biochemical analysis

Increasing plasma triglyceride, cholesterol, glucose and urea nitrogen levels were confirmed in the KK-Ay-Nx and KK-Ay-Nx + NaCl groups.

Plasma biochemical analysis

The 45th Japanese Society of Toxicology (2018)

F4/80 staining

Increasing of mature macrophages were confirmed that was suggested an enhanced inflammatory response.
 F4/80 staining

The 45th Japanese Society of Toxicology (2018)

αSMA staining

αSMA-positive cells were confirmed that was suggested the presence of myofibroblasts.
αSMA staining

The 45th Japanese Society of Toxicology (2018)

Gene expression analysis

Upper: Fibrosis-related genes

Lower: Inflammation-related genes
Gene expression analysis

The 45th Japanese Society of Toxicology (2018)

Correlation diagram (Pathology-Genes)

In the KK-Ay-Nx and the KK-Ay-Nx+NaCl group, increasing IL-1β, TIMP-1, TNFα and type 1 collagen were confirmed.  The pathological scoring also showed the positive correlation results with gene expression.
Correlation diagram (Pathology-Genes)

The 45th Japanese Society of Toxicology (2018)

◆Histopathological analysis

The characteristics of diabetic nephropathy could be seen each place.

 ・Glomerulus: Mesangium hyperplasia

 ・Tubules: degeneration, dilation, Armanni-Ebstein degeneration, urinary cast

 ・Interstitium: αSMA-positive cells, increased macrophages, significant inflammatory cell infiltration and fibrosis

 

HE staining

HE staining

The 45th Japanese Society of Toxicology (2018)

SR staining

SR staining

The 45th Japanese Society of Toxicology (2018)


PAS staining

PAS staining

The 45th Japanese Society of Toxicology (2018)

Nx+NaCl KK-Ay mice had diabetic nephropathy symptoms close to humans.  It is represented a useful model to evaluate drug targeting diabetic nephropathy.

If you are interested, please feel free to contact us from below.

 ・Inquiry

 ・KK-Ay product page


◆Inducing method 2: Diet inducing (QF and WD)

Both type 2 diabetic models, KK-Ay and db/db mouse, were fed QF and WD and compared the effects on the diabetic renal complications.  C57BL/6JJcl mice were used as control animals.

In result, KK-Ay mice showed a higher degree of insulin resistance than db/db mice.  In addition, high-fat diet expedited their nephropathy symptoms. 

 

Study design

9 groups were set. Fed CLEA Japan diet CE-2, QF and WD.

  Animal Feed
Group 1  C57B6  CE-2 
Group 2 C57B6 QF
Group 3 C57B6 WD
Group 4 db/db CE-2
Group 5 db/db QF
Group 6 db/db WD
Group 7 KK-Ay CE-2
Group 8 KK-Ay QF
Group 9 KK-Ay WD

Study design

The 45th Japanese Society of Toxicology (2018)

Body weight and biochemical analysis

KK-Ay mice gained weight without reducing food intake even they were fed cholesterol-added diet. It also showed a high degree of insulin resistance compared to db/db mice.

Body weight and biochemical analysis

The 47th Japanese Society of Toxicology (2020)

Food intake

Food intake

The 47th Japanese Society of Toxicology (2020)

Blood biochemistry

Blood biochemistry
Blood biochemistry

The 47th Japanese Society of Toxicology (2020)

Urinary protein

Urinary protein

The 45th Japanese Society of Toxicology (2018)

◆Analysis of histopathology

PAS staining

Only QF-fed KK-Ay mice had significant glomerular lesion, inflammation, and tubular interstitium.

KK-Ay+QF Group
PAS staining

The 47th Japanese Society of Toxicology (2020)



Scoring

The 47th Japanese Society of Toxicology (2020)

KK-Ay mice showed lower blood glucose and cholesterol levels than db/db mice but significantly higher than control mice.  KK-Ay could be considered as a useful animal model enough for observing diabetic symptoms and complications.

In addition, KK-Ay mice showed a higher insulin resistance level and more enhanced nephropathy by high-fat diet than db/db mice.

It could be considered KK-Ay mouse is a new model of diabetic nephropathy that could evaluate short-term drug efficacy more than db/db mouse.

◆Question / Orders

If you have any question, please feel free to contact us from below.

 ・Inquiry

 ・KK-Ay product page

 ・QF product page



promotion:

Please refer to the below URL if you would like to have more human resembled diabetic nephropathy model, SDT fatty rat, to evaluate drug efficacy study from Hyperfiltration to GFR decreasing phase.

Development of diabetic nephropathy evaluation system using SDT fatty rats: control drug SGLT-2 inhibitor, ACE inhibitor, GLP-1 agonist

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