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Caveolin-1 deficiency protects against mesangial matrix expansion in a mouse model of type 1 diabetic nephropathy

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Abstract

Aims/hypothesis

Glomerular matrix protein accumulation, mediated largely by resident mesangial cells (MCs), is central to the pathogenesis of diabetic nephropathy. We previously showed that caveolin (CAV)-1/caveolae mediate matrix upregulation by MCs in response to high glucose and TGFβ, two important pathogenic mediators of diabetic glomerular sclerosis. Here, we evaluated the in vivo role of CAV-1/caveolae in the development of diabetic nephropathy.

Methods

Diabetes was induced in Cav1-knockout (KO) mice and their wild-type (WT) counterparts by streptozotocin injection. After 10 months, kidneys were evaluated for the development of nephropathy, including glomerular sclerosis and upregulation of matrix proteins. Parallel experiments assessing glucose-induced matrix upregulation were carried out in MCs isolated from KO mice.

Results

KO diabetic mice developed hyperglycaemia and renal hypertrophy, but were protected from developing albuminuria and glomerular sclerosis compared with WT mice. KO mice were significantly protected from the upregulation of glomerular collagen I, fibronectin, connective tissue growth factor (CTGF) and TGFβ. In vitro, glucose induced collagen I A1 promoter activation and collagen I, fibronectin and CTGF protein upregulation in WT but not KO MCs. Re-expression of Cav1 in KO cells restored this response.

Conclusions/interpretation

Cav1 deletion rendered significant protection from glomerular matrix accumulation and albuminuria in a mouse model of type 1 diabetes. These studies provide a foundation for the development of renal-targeted interference with CAV-1/caveolae as a novel approach to the treatment of diabetic nephropathy.

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Abbreviations

AMPK:

AMP-activated protein kinase

CAV:

Caveolin

CSD:

CAV-1 scaffolding domain

CTGF:

Connective tissue growth factor

EM:

Electron microscopy

β-gal:

β-Galactosidase

GST:

Glutathione S-transferase

HG:

High glucose

KO:

Knockout

KO/Cav1 :

KO MCs with Cav1 re-expression

KO/pLHCX:

KO MCs expressing the empty vector pLHCX

MC:

Mesangial cell

MMP:

Matrix metalloproteinase

PAS:

Periodic acid–Schiff’s reagent

PKC:

Protein kinase C

RBD:

Rho-binding domain

RhoA:

Ras homologue gene family, member A

ROS:

Reactive oxygen species

SMAD3:

SMAD family member 3

STZ:

Streptozotocin

VWF:

von Willebrand factor

WT:

Wild-type

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Acknowledgements

We gratefully acknowledge St Joseph’s Healthcare for its support of nephrology research and thank V. Falanga (University of Miami, Miami, FL, USA) for providing the collagen 1 A1 promoter luciferase construct. We also thank M. Walsh (McMaster University) for assistance with statistical analysis for RhoA immunohistochemistry quantification.

Funding

J. C. Krepinsky gratefully acknowledges the financial support of the Canadian Diabetes Association (CDA) and Canadian Institutes of Health Research (CIHR). G. Chen was supported by a Father Sean O’Sullivan Postdoctoral Fellowship.

Duality of interest

The authors declare there is no duality of interest associated with this manuscript.

Contribution statement

THG, GC, BG, AJI, MRJ and LU acquired data. THG and JCK performed data analysis and interpretation. JCK was responsible for the conception of the study and drafting the article. All authors provided critical input to revision of the draft and approved the final version.

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Authors and Affiliations

  1. Division of Nephrology, McMaster University, St Joseph’s Hospital, 50 Charlton Ave East, Rm T3311, Hamilton, ON, Canada, L8N 4A6

    T. H. Guan, G. Chen, B. Gao, M. R. Janssen, L. Uttarwar, A. J. Ingram & J. C. Krepinsky

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  1. T. H. Guan
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  2. G. Chen
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  3. B. Gao
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  4. M. R. Janssen
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  7. J. C. Krepinsky
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Correspondence to J. C. Krepinsky.

Additional information

T. H. Guan and G. Chen contributed equally to this study

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Guan, T.H., Chen, G., Gao, B. et al. Caveolin-1 deficiency protects against mesangial matrix expansion in a mouse model of type 1 diabetic nephropathy. Diabetologia 56, 2068–2077 (2013). https://doi.org/10.1007/s00125-013-2968-z

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