We have recently identified that circulating adiponectin levels negatively correlate with albuminuria in obese African Americans. As the incidence of kidney disease is extremely high in African Americans and the mechanisms of obesity related kidney disease are unclear, our proposal will focus on this highly significant topic to the VA population. The podocyte appears to be the main target cell by which adiponectin confers its protective action. In the present proposal we will identify the adiponectin receptors and signaling pathways by which adiponectin confers benefits to the podocytes and examine the key role of adiponectin in regulating an enzyme called AMPK. We have identified that AMPK is decreased in adiponectin deficient mice and in podocytes from diabetic mice. Administration of adiponectin restores AMPK activity and appears to protect podocytes from albuminuria. A key target of AMPK on podocytes appears to be the protein ZO-1 which has been shown to be intimately involved in the adherence of the podocyte foot processes to the glomerular basement membrane. The proposal aims to identify the key signaling receptors for adiponectin on podocytes, identify the role of AMPK and identify the proteins regulated by adiponectin and AMPK in mice. The studies will be of direct benefit to the VA population as there are existing drugs that regulate adiponectin levels and its signaling pathways, and thus may potentially offer new therapies for this population that is at high risk for kidney disease.
Project Narrative There are over 60-80 million Americans with obesity, diabetes and hypertension. Many of them have evidence of early kidney disease. We have recently identified that a hormone produced by the fat cells, called adiponectin appears to be a major contributor to the early kidney disease seen in patients with obesity. Our recent studies have identified that the podocyte is a key target cell of adiponectin action. Our studies will determine the role of adiponectin in podocytes of the kidney. By understanding the relationships between adiponectin, its receptors, AMPK and ZO-1 we expect that new treatments will arise that can treat these patients at early stages. The availability of available drugs that regulate the AMPK pathway is an indication of the translation potential of our work.
|Miyamoto, Satoshi; Hsu, Cheng-Chih; Hamm, Gregory et al. (2016) Mass Spectrometry Imaging Reveals Elevated Glomerular ATP/AMP in Diabetes/obesity and Identifies Sphingomyelin as a Possible Mediator. EBioMedicine 7:121-34|
|Saito, Rintaro; Rocanin-Arjo, Anaïs; You, Young-Hyun et al. (2016) Systems biology analysis reveals role of MDM2 in diabetic nephropathy. JCI Insight 1:e87877|
|Declèves, Anne-Emilie; Sharma, Kumar (2015) Obesity and kidney disease: differential effects of obesity on adipose tissue and kidney inflammation and fibrosis. Curr Opin Nephrol Hypertens 24:28-36|
|Börgeson, Emma; Johnson, Andrew M F; Lee, Yun Sok et al. (2015) Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease. Cell Metab 22:125-37|
|Declèves, Anne-Emilie; Zolkipli, Zarazuela; Satriano, Joseph et al. (2014) Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int 85:611-23|
|Sharma, Kumar (2014) Obesity, oxidative stress, and fibrosis in chronic kidney disease. Kidney Int Suppl (2011) 4:113-117|
|Sharma, Kumar; Karl, Bethany; Mathew, Anna V et al. (2013) Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol 24:1901-12|