Increased matrix metalloproteinase expression in kidney tissue from prediabetic but not diabetic mice: possible role in protection from matrix accumulation. — ASN Events
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Increased matrix metalloproteinase expression in kidney tissue from prediabetic but not diabetic mice: possible role in protection from matrix accumulation. (#229)

Anh Tao 1 , Linda Ban 1 , Rebecca Seehoo 1 , Surya Sutanto 1 , Babu Raja Maharjan 1 , Danqing Min 1 2 , Stephen Twigg 1 2 , Susan McLennan 1 2
  1. Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School, Charles Perkins Centre and Bosch Institute, University of Sydney , Sydney, NSW, Australia
  2. Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Matrix accumulation is a hallmark of diabetic nephropathy with alterations in both synthetic and degradative pathways being described. The matrix metalloproteinases (MMPs) are important for maintenance of matrix turnover but they have not been systematically examined in prediabetic and diabetic states. In this cross sectional study we investigated the expression of a panel of MMPs and their relationship with markers of fibrosis in obese and diabetic mice.

Mice were fed a HFD (45%kCal fat) after 15 weeks some mice were made diabetic (HFD+DM: 3x65mg/kg STZ), age matched diabetic (DM), and non-diabetic (CHOW) animals acted as control. All animals were terminated after an additional 38 weeks and kidney tissue was harvested for measurement MMPs (MMPs -2,-3,-7,-8,-9, 14) and fibrosis markers (fibronectin and collagen Iα1) by qRT-PCR and histology. Blood was collected for measurement of circulating insulin level .

As expected, HFD mice were significantly heavier (P<0.001), had lower kidney to body weight ratio (by 0.5 fold, P<0.001) and increased circulating insulin (by 6 fold, P<0.02) than all other groups. The expression of fibronectin and collagen Iα1 was increased by DM and HFD+DM (both P<0.001 vs CHOW), but in HFD animals only fibronectin was increased (P<0.02 vs CHOW).  The expression of MMP-3 was increased across all groups reaching significance for HFD. MMP-2 was increased and MMP-9 was decreased in HFD and HFD+DM animals, whilst MMP-7 and MMP-14 were both elevated by diabetes.By histology, the HFD+DM group showed the most pronounced pathology which included inflammatory cell infiltration, glomerular matrix accumulation, and loss of tubular morphology.

This study shows that MMP expression profiles are affected by diet, diabetes presence and stage of disease. As MMP system plays an important role in maintenance of extracellular matrix, how these changes relate to development of kidney changes may have utility for future strategies to monitor or prevent disease.

MMP-2

MMP-3

MMP-7

MMP-8

MMP-9

MMP-14

CHOW

1.0±0.29

1.0±0.77

1.0±0.57

1.0±0.32

1.0±0.56

1.0±0.40

HFD

1.79±0.67*

3.73±1.19#

0.71±0.54

1.15±0.26

0.56±0.26

0.93±0.41

DM

0.85±0.70

1.88±0.96

1.83±1.43

0.72±0.50

1.60±1.32

3.07±2.27

HFD+DM

1.41±2.14

1.83±1.59

10.20±12.18

1.25±1.99

0.43±0.17

1.81±0.50*

 Results are Mean ± SD, *P<0.05, #P<0.001 vs control T-Test