Diabetic Nephropathy (DN) is the largest single cause of end-stage renal disease in the United States. Current therapies for diabetes are not effective in reversing established complications such as DN. We have recently reported a new murine model of DN, the BTBR mouse strain with the ob/ob leptin deficiency mutation that closely resembles human DN including early loss of podocytes (podo). We present preliminary data clearly demonstrating that reversibility of nephropathy can be achieved in our model. In this proposal, we build upon these observations to define and optimize strategies for reversal of DN with a focus on two fundamental mechanisms that may be pivotal in the pathogenesis of DN and its reversal: depletion of podos and their regeneration. We show in our model exciting data that podocyte number can be restored with reversal of DN. In our first specific aim, we develop a strategy to identify the source of the regenerating podos. Using lineage tracing studies, we will test whether neighboring parietal epithelial cells PECs can serve as a local progenitor cell niche for regenerating podos. We will test several interventions including commonly used therapies for human DN to test whether their lack of efficacy for reversal of DN is linked with their inability to promote restoration of podo #. We will extend our observations to human kidney biopsies of DN to directly translate our observations in mice to the human disease. In our second specific aim, we will investigate mechanisms that potentiate podo loss and those that facilitate regeneration, focusing on injury induced by mitochondrial oxidative stress induced by reactive oxygen species (mtROS), considered a principal cause of podocyte injury in DN. We utilize strategies of podocyte specific and systemic scavenging of mtROS to test whether these approaches can abrogate progression of DN and/or promote its reversal in conjunction with restoration of podo #. We pursue these strategies both by creation of transgenic mice that inducibly overexpress the ROS scavenger catalase in a mitochondrially restricted fashion, as well as by administration of novel peptides characterized by their ability to reduce mitochondrial oxidative stress. In aggregate, the proposed studies will enable testing of our central hypothesis: loss of podos is an early and proximate step in the development of the characteristic lesions of DN, that further podo loss and renewal are concurrently active processes, that prevention of podo loss substantially limits the development of DN, and ultimately that repair of DN requires restoration of podo number. The impact of these studies will be 1) to establish new paradigms that podo regeneration in DN can be achieved, and that place a new emphasis on PECs in the evolution and repair of DN. 2) to establish for the first time a mechanism by which podo regeneration is accomplished and by which reversal of DN may be achieved, by employing highly specific tests of whether mtROS injuries to podos are causal and required for the development of DN. 3) If successful, restoration of podo loss by a novel small molecule inhibitor of mtROS could serve as a proof of principle for a new class of therapeutic agents with potential to reverse human DN.
These studies use a new mouse model of diabetic kidney disease characterized by our laboratory (the BTBR mouse strain with leptin deficiency) that is reversible when leptin is replaced. This grant explores mechanisms underlying reversibility (replacement of kidney cell populations that are typically lost in human and experimental diabetic kidney disease) with emphasis on the podocyte, a unique cell type in the kidney. We then will test new therapies, based on correcting metabolic injuries to mitochondria (an organelle present within all cells), that are specifically directed to podocyte mitochondria, as a way to promote reversal of diabetic kidney disease.
| Anderberg, Robert J; Meek, Rick L; Hudkins, Kelly L et al. (2015) Serum amyloid A and inflammation in diabetic kidney disease and podocytes. Lab Invest 95:250-62 |
| Andeen, Nicole K; Nguyen, Tri Q; Steegh, Floor et al. (2015) The phenotypes of podocytes and parietal epithelial cells may overlap in diabetic nephropathy. Kidney Int 88:1099-107 |
| Eom, Minseob; Hudkins, Kelly L; Alpers, Charles E (2015) Foam cells and the pathogenesis of kidney disease. Curr Opin Nephrol Hypertens 24:245-51 |
| Zhi, Zhongwei; Chao, Jennifer R; Wietecha, Tomasz et al. (2014) Noninvasive imaging of retinal morphology and microvasculature in obese mice using optical coherence tomography and optical microangiography. Invest Ophthalmol Vis Sci 55:1024-30 |
| Pippin, Jeffrey W; Glenn, Sean T; Krofft, Ronald D et al. (2014) Cells of renin lineage take on a podocyte phenotype in aging nephropathy. Am J Physiol Renal Physiol 306:F1198-209 |
| Reddy, Marpadga A; Sumanth, Putta; Lanting, Linda et al. (2014) Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 85:362-73 |
| Askari, Bardia; Wietecha, Tomasz; Hudkins, Kelly L et al. (2014) Effects of CP-900691, a novel peroxisome proliferator-activated receptor ?, agonist on diabetic nephropathy in the BTBR ob/ob mouse. Lab Invest 94:851-62 |
| Gharib, Sina A; Pippin, Jeffrey W; Ohse, Takamoto et al. (2014) Transcriptional landscape of glomerular parietal epithelial cells. PLoS One 9:e105289 |
| Pichaiwong, Warangkana; Hudkins, Kelly L; Wietecha, Tomasz et al. (2013) Reversibility of structural and functional damage in a model of advanced diabetic nephropathy. J Am Soc Nephrol 24:1088-102 |
| Brosius 3rd, Frank C; Alpers, Charles E (2013) New targets for treatment of diabetic nephropathy: what we have learned from animal models. Curr Opin Nephrol Hypertens 22:17-25 |
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