Type 2 Diabetes and Nephropathy in db/db Mice: Role of MKK3-p38 MAPK Signaling

Andy K.H. Lim, David Nikolic-Paterson, Frank Y. Ma, Eliyce Ozols, Richard A Flavell, Roger Davis, Greg Tesch

Research output: Contribution to conferenceAbstract


Increased intracellular p38 mitogen-activated protein kinase (MAPK) signaling occurs with obesity and diabetes, and may promote tissue inflammation and injury. Although p38 MAPK can be activated by either of the two upstream kinases (MKK3 or MKK6), recent evidence suggests that MKK3 has non-redundant roles in pathological p38 MAPK activation. The aim of this study was to determine whether MKK3 deficiency affects the development of obesity, type 2 diabetes and diabetic nephropathy. C57BL/6 db/db mice deficient in the Mkk3 gene were assessed between 8 and 32 weeks of age. Mkk3+/+ db/ db and Mkk3-/- db/db mice developed equivalent obesity and an equivalent incidence and severity of diabetes. Kidney levels of phospho-p38 and MKK3 protein were increased in diabetic Mkk3+/+ db/db mice but remained normal in diabetic Mkk3-/- db/db mice despite a 4-fold compensatory increase in MKK6 protein. Reduced p38 MAPK signaling in Mkk3- /- db/db mice was associated with a reduction in albuminuria, podocyte loss, mesangial cell activation and glomerular fibrosis. MKK3 deficiency also protected diabetic db/db mice from tubular injury and interstitial fibrosis, which was associated with reduced kidney levels of MCP-1 and interstitial macrophage accumulation. Thus, MKK3-p38 MAPK signaling is not required for the development of obesity or type 2 diabetes but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice. Disclosure of Financial Relationships: grant/research support: Celgene; consultant: Celgene, Johnson & Johnson; honoraria: Celgene; advisory board or board of directors: Johnson&Johnson
Original languageEnglish
Number of pages1
Publication statusPublished - Nov 2008
EventAnnual Scientific Meeting of the American Society of Nephrology 2008 - Pennsylvania Convention Center, Philadelphia, United States of America
Duration: 4 Nov 20089 Nov 2008


ConferenceAnnual Scientific Meeting of the American Society of Nephrology 2008
Country/TerritoryUnited States of America

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