Heterozygosity of mitogen-activated protein kinase organizer 1 ameliorates diabetic nephropathy and suppresses epithelial-to-mesenchymal transition-like changes in db/db mice.
Background
Progressive diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis that is caused by accumulation of extracellular matrix. Induced by several factors, matrix-producing myofibroblasts may to some extent originate from tubular cells by epithelial-to-mesenchymal transition (EMT). Although previous data document that activation of hypoxia-inducible factor (HIF) signalling can be renoprotective in acute kidney disease, this issue remains controversial in chronic kidney injury. Here, we studied whether DN and EMT-like changes are ameliorated in a mouse model of type 2 diabetes mellitus with increased stability and activity of the HIF.


Methods
We used db/db mice that were crossed with transgenic mice expressing reduced levels of mitogen-activated protein kinase organizer 1 (MORG1), a scaffold protein interacting with prolyl hydroxylase domain 3 (PHD3), because of deletion of one MORG1 allele.


Results
We found significantly reduced nephropathy in diabetic MORG1+/- heterozygous mice compared with the diabetic wild-types (db/dbXMORG1+/+). Furthermore, we demonstrated that EMT-like changes in the tubulointerstitium of diabetic wild-type MORG1+/+ mice are present, whereas diabetic mice with reduced expression of MORG1 showed significantly fewer EMT-like changes.


Conclusions
These findings reveal that a deletion of one MORG1 allele inhibits the development of DN in db/db mice. The data suggest that the diminished interstitial fibrosis in these mice is a likely consequence of suppressed EMT-like changes.
['Loeffler|Ivonne|I|', 'Liebisch|Marita|M|', 'Daniel|Christoph|C|', 'Amann|Kerstin|K|', 'Wolf|Gunter|G|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D003921:Diabetes Mellitus, Experimental D003924:Diabetes Mellitus, Type 2 D003928:Diabetic Nephropathies D004195:Disease Models, Animal D058750:Epithelial-Mesenchymal Transition D006579:Heterozygote D051379:Mice D008810:Mice, Inbred C57BL D008815:Mice, Inbred Strains D008822:Mice, Transgenic D015398:Signal Transduction
diabetic nephropathy (DN) epithelial-to-mesenchymal transition (EMT) HIF (hypoxia-inducible factor) MORG1 (MAPK organizer 1)