Journal Article Ppublish 2 citations
PubMed: 39874092 DOI: 10.1681/ASN.0000000611
Integrin Trafficking, Fibronectin Architecture, and Glomerular Injury upon Adiponectin Receptor 1 Depletion.
J Am Soc Nephrol 36(5):825-844
Authors: Sonja Lindfors, Constanze Schmotz, Dominik Lewandowski, Annika Hau, Leena Saikko, Eero Lehtonen, Ville Majaniemi, Minna Karhe, Jette-Britt Naams, Harry Nisen, Jukka Tienari, Moin A Saleem, Katharina Pfeil, Heiko Bugger, Kirsi H Pietiläinen, Tuomas Mirtti, Krzysztof Palczewski, Sanna Lehtonen
Affiliations
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, Irvine, California.
- Department of Pathology, University of Helsinki, Helsinki, Finland.
- Abdominal Center, Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
- Department of Cardiology, Medical University of Graz, Graz, Austria.
- Obesity Research Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Healthy Weight Hub, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, California.
- Department of Chemistry, University of California, Irvine, Irvine, California.
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California.
Abstract
BACKGROUND
Deficiency of adiponectin and its downstream signaling may contribute to the pathogenesis of kidney injury in type 2 diabetes. Adiponectin activates intracellular signaling via adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2), but the role of AdipoR-mediated signaling in glomerular injury in type 2 diabetes remains unknown.
METHODS
The expression of AdipoR1 in the kidneys of people with type 2 diabetes and the expression of podocyte proteins or injury markers in the kidneys of AdipoR1-knockout (AdipoR1-KO) mice and immortalized AdipoR1-deficient human podocytes were investigated by immunohistochemistry and immunoblotting. The functional role of AdipoR1 was studied in AdipoR1-deficient podocytes by performing assays for apoptosis, cytokine secretion, mechanical stress, adhesion, and endocytic trafficking.
RESULTS
Glomerular AdipoR1 expression was lower in type 2 diabetes and associated kidney disease, correlating with higher BMI and podocyte loss. Male AdipoR1-KO mice showed typical signs of early diabetic kidney disease, including albuminuria, glomerular structural abnormalities, and lower expression of central podocyte proteins; females were less affected. Podocyte apoptosis increased in female and male AdipoR1-KO mice and excessive podocyte loss, potentially due to detachment, was detected in males. AdipoR1 deficiency impaired the YAP-mediated mechanoresponse and induced accumulation of the extracellular matrix (ECM) protein fibronectin in the glomeruli in vivo, and podocytes in vitro. Functionally, AdipoR1 deficiency impaired endocytosis of the ECM receptor active integrin β1, disturbed focal adhesion turnover, and remodulated podocyte-derived ECM, thereby reducing podocyte adhesion.
CONCLUSIONS
AdipoR1 deficiency in mice resulted in the development of kidney injury predominantly in males. Mechanistically, AdipoR1 loss in podocytes impaired endocytosis of active integrin β1, which plausibly compromised focal adhesion dynamics, disturbed fibronectin matrix turnover, and hindered podocyte adhesion.
MeSH
Diabetes Mellitus, Kidney Diseases, Tissue Adhesions, Receptors, Adiponectin, Integrins, Podocytes, Diabetic Nephropathies, Adiponectin, Kidney, Nephrology, Fibronectins, Apoptosis, Focal Adhesions, Endocytosis, Diabetes Mellitus, Type 2