Chronic kidney disease (CKD), end stage renal disease and their complications are a public health problem of epidemic proportions. CKD afflicts more individuals over 65 years old than diabetes or congestive heart failure, approximately 40% of older patients. Postulated explanations for increased susceptibility to renal failure with increasing age include the high frequency of diabetes and ischemia. Our preliminary data support the clinically relevant hypothesis that ischemia accelerates the progression of nephropathy in the aged kidney by activating proinflammatory pathways in tubular epithelia ultimately resulting in apoptotic cell death, fibrosis and renal failure. Furthermore, we have demonstrated critical roles for the proinflammatory receptors intercellular adhesion molecule-1 (ICAM-1) and lectin-like oxidized low density lipoprotein receptor (LOX-1) in this postischemia inflammatory syndrome. We now postulate that both systemic, particularly interleukins (interleukin)-1 and -6, and intrarenal (angiotensin II and p38 mitogen activated protein kinase) mediators regulate ICAM-1 and LOX-1 and therefore inflammation and function in the aged, diabetic postischemia kidney. To directly test our hypotheses, we propose the following specific aims: (To determine the mechanisms by which metabolic derangements and hypoxia result in tubular epithelial activation to a proinflammatory phenotype. We have demonstrated activation of tubular epithelia to a proinflammatory state with upregulation of ICAM-1 and LOX-1 both in vivo in diabetes/obesity and in vitro in cultured renal tubular epithelial cells exposed to proinflammatory lipids. Using this cell culture model to define the mechanisms of ICAM-1 and LOX-1 regulation and alteration of function will allow control of more factors and the use of specific blockers to thoroughly dissect the mechanisms of inflammation and injury. We will determine the key mediators of induction of ICAM-1 and LOX-1 in these cells and evaluate inhibitors for potential use in vivo. (To define the mechanisms of renal inflammation, particularly tubular induction of ICAM-1 and LOX-1, in the postischemia inflammatory syndrome in the aged ZS rat kidney. We hypothesize that systemic interleukin (IL)-1, IL-6, as early regulators;and intrarenal p38 mitogen activated protein kinase (MAPK) and angiotensin II, as amplifiers, are critical in ICAM-1 and LOX-1 expression in renal tubules in chronic kidney disease. Furthermore, we propose that blocking inflammation with mycophenolate mofetil or specific inhibition of ICAM-1, IL-1, angiotensin II or p38 MAPK will ameliorate renal injury in the postischemia inflammatory syndrome in the aging, diabetic kidney. Finally, we will evaluate tubular cell transplantation as an innovative therapy for renal failure. The proposed studies examine the novel hypothesis that age-related renal disease results (at least in part) from inflammation, including that mediated by ICAM-1 and LOX-1;that IL-1, IL-6, p38 MAPK and angiotensin II are critical in the induction of ICAM-1 and LOX-1 and that specific blockers of inflammation will result in improved function in the postischemia inflammatory syndrome in the aged kidney.

Public Health Relevance

Chronic kidney disease (CKD) in those older than 60 years has increased markedly to approximately 28% of the population. In the US, more people are afflicted with CKD than either diabetes or congestive heart failure. Nearly one-half of patient beginning dialysis for CKD were e65 yo. We propose to study inflammatory and vascular injury and cell death and the effects of potential therapies in a model of CKD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Rys-Sikora, Krystyna E
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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Dominguez 2nd, James M; Dominguez, Jesus H; Xie, Danhui et al. (2018) Human extracellular microvesicles from renal tubules reverse kidney ischemia-reperfusion injury in rats. PLoS One 13:e0202550
Kelly, K J; Zhang, Jizhong; Han, Ling et al. (2015) Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy. PLoS One 10:e0131677
Kelly, Katherine J; Liu, Yunlong; Zhang, Jizhong et al. (2015) Renal C3 complement component: feed forward to diabetic kidney disease. Am J Nephrol 41:48-56
Kelly, K J; Liu, Yunlong; Zhang, Jizhong et al. (2013) Comprehensive genomic profiling in diabetic nephropathy reveals the predominance of proinflammatory pathways. Physiol Genomics 45:710-9
Kelly, Katherine J; Zhang, Jizhong; Han, Ling et al. (2013) Intravenous renal cell transplantation with SAA1-positive cells prevents the progression of chronic renal failure in rats with ischemic-diabetic nephropathy. Am J Physiol Renal Physiol 305:F1804-12
Kelly, Katherine J; Zhang, Jizhong; Wang, Mingsheng et al. (2012) Intravenous renal cell transplantation for rats with acute and chronic renal failure. Am J Physiol Renal Physiol 303:F357-65