Inflammation and the innate immune system have long been known to play a major role in many types of chronic kidney diseases. More recently, their involvement has been extended to include roles in diabetic nephropathy and even damage due to aging. We have been studying kidney damage in mouse models with different levels of growth hormone (GH) signaling ranging from over-expression to complete lack of GH signaling. Mice with above normal levels of GH signaling spontaneously develop kidney damage, progressing in severity with increasing age. Mice with reduced or no GH signaling are protected from damage, even when diabetes is induced. We and others have observed that levels of inflammatory markers are increased in the kidneys of the mice with increased GH signaling, indicating a positive correlation between GH signaling, inflammation and kidney damage. Our overall goal is to study the relationship between GH signaling and inflammation in nephropathy. For this proposal we wish to test two hypotheses: 1) Expression of inflammatory markers will be reduced in kidneys of diabetic mice with disrupted GH signaling, as compared to expression in diabetic mice with intact GH signaling;and 2) Direct induction by cytokines of expression of inflammatory markers in isolated glomeruli, or primary cell cultures or cell lines derived from isolated glomeruli (i.e. mesangial cells and podocytes), will depend on an intact GH signaling pathway. To test the first hypothesis, we will induce diabetes in growth hormone receptor/binding protein knock-out (GHR/BP KO) mice, which lack GH signaling, and their non-transgenic (NT) littermates, which have intact GH signaling, by injection of streptozotocin, resulting in type 1 diabetes. After 10 weeks, we will measure both RNA and protein levels of multiple inflammatory markers within the kidneys. The changes in expression will be correlated with changes in kidney morphology and function as well as with GH signaling capability. To test the second hypothesis, we will treat glomeruli and primary cell cultures or cell lines (mesangial and podocyte), isolated from NT and GHR/BP KO mice, with cytokines that are key mediators of inflammation (e.g. TNF-alpha, IL-6, TGF-beta1) and measure expression of cellular inflammatory markers as described above, correlating any changes in expression levels with GH signaling capability. The identification of cross-talk between GH signaling and inflammation pathways in kidney damage will aid in the design of specific, targeted approaches for the diagnosis, treatment or prevention of nephropathy. This project also provides many facets of learning opportunities for undergraduate, graduate and medical students working in the laboratory, including underrepresented minorities. This exposure to biomedical research will provide them with a solid foundation upon which they can build a career in the health-related fields.
This project investigates an important health issue, kidney damage resulting from diabetes. The knowledge gained should provide specific, targeted approaches for the diagnosis, treatment or prevention of diabetic kidney damage. Furthermore, this project provides an excellent training environment for undergraduate, graduate and medical students, including underrepresented minorities, as they pursue careers in the health-related fields.
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| McCall, Kelly D; Thuma, Jean R; Courreges, Maria C et al. (2015) Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice. Endocrinology 156:453-61 |
| McCall, Kelly D; Schmerr, Martin J; Thuma, Jean R et al. (2013) Phenylmethimazole suppresses dsRNA-induced cytotoxicity and inflammatory cytokines in murine pancreatic beta cells and blocks viral acceleration of type 1 diabetes in NOD mice. Molecules 18:3841-58 |
| Coschigano, K T; Wetzel, A N; Obichere, N et al. (2010) Identification of differentially expressed genes in the kidneys of growth hormone transgenic mice. Growth Horm IGF Res 20:345-55 |
