Tubulointerstitial fibrosis is a prominent pathological feature of progressive renal disease including diabetic nephropathy. In diabetic nephropathy and other progressive renal diseases, tubular epithelial cells acquire mesenchymal cell characteristics and accumulate matrix proteins that eventuate in fibrosis. Two potential mediators of renal fibrosis in diabetes are high glucose concentrations and transforming growth factor-beta. We have evidence that glucose and TGF-beta inactivate the energy sensor AMPK and that this may result in the cells acquiring mesenchymal cell characteristics and accumulating matrix proteins. The work proposed in this application will utilize in vitro and in vivo approaches to establish if AMPK is indeed a modulator of renal fibrosis and identify downstream signal transduction pathway(s) that may be the effectors of AMPK. Pharmacological and genetic approaches will be used to activate or inhibit AMPK in vitro in cultured tubular epithelial cells. For the in vivo studies, we will utilize mice deficient in AMPK specifically in proximal tubular tubular cells. In addition, OVE26 mice with type 1 diabetes will b used to investigate the role of AMPK and downstream signaling pathways including tuberin and mTOR . The central hypothesis of this proposal is that AMPK regulates matrix protein accumulation and mesencymal characteristics of tubular epithelium in diabetes. The studies will help establish adjunct therapy in addition to metabolic control to treat the complications of diabetes.
Metabolic control of diabetes remains the most effective approach to prevent the development diabetic complications including diabetic nephropathy. However, achieving euglycemia is difficult and may be associated with complications. Understanding cellular mechanisms that contribute to the pathogenesis and progression of diabetic nephropathy may help develop adjunct therapy to prevent or even reverse this complication of diabetes. Interstitial fibrosis is a prominent feature of diabetic nephropathy. We have evidence that AMPK, an energy sensor in cells and tissues, regulate matrix protein accumulation and other mesenchymal features of tubular epithelial cells in diabetes. We wish to explore the role of this kinase and identify its mechanisms of action. The studies may result in the identification of new therapeutic strategies to treat diabetic nephropathy. Specifically, the work may demonstrate the utility of AMPK activators to prevent diabetic complications not only in type 2 but also in type1 diabetes.
|Nayak, Bijaya K; Shanmugasundaram, Karthigayan; Friedrichs, William E et al. (2016) HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice. Diabetes 65:1387-97|
|Souto Padron de Figueiredo, Alvaro; Salmon, Adam B; Bruno, Francesca et al. (2015) Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet. J Biol Chem 290:13427-39|
|Gorin, Yves; Cavaglieri, Rita C; Khazim, Khaled et al. (2015) Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes. Am J Physiol Renal Physiol 308:F1276-87|
|Zhao, Qingwei David; Viswanadhapalli, Suryavathi; Williams, Paul et al. (2015) NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFÎºB signaling pathways. Circulation 131:643-55|
|Thameem, Farook; Voruganti, V Saroja; Blangero, John et al. (2015) Evaluation of neurotrophic tyrosine receptor kinase 2 (NTRK2) as a positional candidate gene for variation in estimated glomerular filtration rate (eGFR) in Mexican American participants of San Antonio Family Heart study. J Biomed Sci 22:23|
|Thakur, Sachin; Viswanadhapalli, Suryavathi; Kopp, Jeffrey B et al. (2015) Activation of AMP-activated protein kinase prevents TGF-Î²1-induced epithelial-mesenchymal transition and myofibroblast activation. Am J Pathol 185:2168-80|
|Beck Gooz, Monika; Maldonado, Eduardo N; Dang, Yujing et al. (2014) ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease. Am J Physiol Renal Physiol 307:F551-9|
|SIGMA Type 2 Diabetes Consortium; Estrada, Karol; Aukrust, Ingvild et al. (2014) Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA 311:2305-14|
|Bera, Amit; Das, Falguni; Ghosh-Choudhury, Nandini et al. (2014) microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKÎ²-mTORC1 axis to regulate renal cancer cell invasion. Exp Cell Res 328:99-117|
|Bera, Amit; Das, Falguni; Ghosh-Choudhury, Nandini et al. (2014) A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF. Am J Physiol Cell Physiol 306:C1089-100|
Showing the most recent 10 out of 70 publications