This project, in part, represents an extension of work previously reported as Project Number Z01 DK69037. Glomerular function was measured initially over a 4-year period in 194 Pima Indians selected to represent stages in the development and progression of diabetic renal disease. Eighty-six of these subjects had type 2 diabetes and micro- or macroalbuminuria. Subjects underwent serial determinations of albuminuria and GFR. Many of these subjects continue to be followed and we have accumulated over 19 years of data on glomerular hemodynamic function in these patients. We also follow a population-based cohort of Pima Indians who are invited every two years to participate in a research examinination. The methods for this longitudinal study are described in detail in Project Numbers Z01 DK069097 and Z01 DK069000 Urinary albumin-to-creatinine ratios and serum creatinine concentration are measured at each of these examinations, and participants who progress to kidney failure are identified. In the past year, we found that greater ACR predicted diabetic ESRD and natural mortality in Pima Indians with type 2 diabetes. The incidence of diabetic ESRD was nearly 2 times as high and the death rate was 1.2 times as high with each 2-fold increment in the latest ACR level. Although past measurements were related to these outcomes, they did not add to the predictive power when the current measurement was considered. A low current ACR value was associated with good prognosis regardless of whether earlier values were higher, the same, or lower. Therefore, changes in ACR over time, ie, regression or progression, added minimal predictive value beyond the latest measurement in the series. We found that in diabetes, as assessed by microarray analysis of kidney biopsy tissue and confirmed by RT-PCR and immunohistochemistry, the Jak/Stat signaling pathway appears to be involved with the development and progression of diabetic nephropathy. Our findings suggest an interesting compartmental and temporal association of enhanced Jak2 expression. Glomerular Jak2 mRNA levels increase several-fold in diabetic patients with early DN and then decline in later stages as tubulointerstitial Jak2 increases along with progressive tubulointerstitial fibrosis and reduction in kidney function. Thus, enhanced Jak2 expression temporally corresponds to the evolution of human DN, with glomerulopathy followed by tubulointerstitial fibrosis. The strong correlation between tubulointerstitial Jak2 expression and that of other Jak/Stat members with serum creatinine suggests a potential causal relationship between enhanced Jak2 expression and progressive tubulointerstitial fibrosis and renal failure. Expression profiling of patients with diabetic nephropathy identified CD74 as an overexpressed glomerular molecule. As a receptor for macrophage migration inhibitory factor (MIF), CD74 could contribute to podocyte injury in susceptible patients with diabetes by activating MAPK cascades and increasing TNF-related apoptosis inducing ligand (TRAIL) and MCP-1 expression. In the coming year, we will characterize, among other things, the frequency and impact of low glomerular filtration rate in diabetic persons with normal urinary albumin excretion to determine whether these persons are at different risk for progression of kidney disease than those with elevated urinary albumin excretion. We will examine the effect of alcohol intake on development and progression of diabetic kidney disease and determine the predictive value of elevated urinary albumin excretion for progressive kidney disease in children and adolescents. Changes in management of diabetic kidney disease will be examined to determine whether improvements in health services are reflected by improvements in blood pressure, glycemic, and lipid control. Changes in glomerular hemodynamics will be examined relative to structural damage identified by morphometric evaluation of kidney biopsies as reported in Project Number Z01 DK069100. This project continues to yield new insights into the pathogenesis, course, and management of kidney disease in type 2 diabetes. Characterization of hemodynamic function over prolonged periods, combined with detailed clinical information derived from ongoing epidemiologic evaluation have greatly enriched the value of this data resource for studying diabetic kidney disease.
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