RESUMO
Diabetic kidney disease is the leading cause of kidney failure. However, studies of molecular mechanisms of early kidney damage are lacking. Here we examined for possible linkage between transcriptional regulation and quantitative structural damage in early diabetic kidney disease in Pima Indians with type 2 diabetes. Tissue obtained from protocol kidney biopsies underwent genome-wide compartment-specific gene expression profiling and quantitative morphometric analysis. The ultrastructural lesion most strongly associated with transcriptional regulation was cortical interstitial fractional volume (VvInt), an index of tubule-interstitial damage. Transcriptional co-expression network analysis identified 1843 transcripts that correlated significantly with VvInt. These transcripts were enriched for pathways associated with mitochondrial dysfunction, inflammation, migratory mechanisms, and tubular metabolic functions. Pathway network analysis identified IL-1ß as a key upstream regulator of the inflammatory response and five transcription factors cooperating with p53 to regulate metabolic functions. VvInt-associated transcripts showed significant correlation with the urine albumin to creatinine ratio and measured glomerular filtration rate 10 years after biopsy, establishing a link between the early molecular events and long-term disease progression. Thus, molecular mechanisms active early in diabetic kidney disease were revealed by correlating intrarenal transcripts with quantitative morphometry and long-term outcomes. This provides a starting point for identification of urgently needed therapeutic targets and non-invasive biomarkers of early diabetic kidney disease.
Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Perfilação da Expressão Gênica/métodos , Rim/química , RNA Mensageiro/genética , Transcrição Gênica , Adulto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/terapia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etnologia , Nefropatias Diabéticas/terapia , Progressão da Doença , Feminino , Redes Reguladoras de Genes , Marcadores Genéticos , Predisposição Genética para Doença , Taxa de Filtração Glomerular/genética , Humanos , Indígenas Norte-Americanos/genética , Rim/ultraestrutura , Masculino , Pessoa de Meia-Idade , Fenótipo , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/genética , Fatores de Tempo , Transcriptoma , Estados Unidos/epidemiologiaRESUMO
Diabetic kidney disease (DKD) is a microvascular complication of type 1 and 2 diabetes with a devastating impact on individuals with the disease, their families, and society as a whole. DKD is the single most frequent cause of incident chronic kidney disease cases and accounts for over 40% of the population with end-stage renal disease. Contributing factors for the high prevalence are the increase in obesity and subsequent diabetes combined with an improved long-term survival with diabetes. Environment and genetic variations contribute to DKD susceptibility and progressive loss of kidney function. How the molecular mechanisms of genetic and environmental exposures interact during DKD initiation and progression is the focus of ongoing research efforts. The development of standardized, unbiased high-throughput profiling technologies of human DKD samples opens new avenues in capturing the multiple layers of DKD pathobiology. These techniques routinely interrogate analytes on a genome-wide scale generating comprehensive DKD-associated fingerprints. Linking the molecular fingerprints to deep clinical phenotypes may ultimately elucidate the intricate molecular interplay in a disease stage and subtype-specific manner. This insight will form the basis for accurate prognosis and facilitate targeted therapeutic interventions. In this review, we present ongoing efforts from large-scale data integration translating "-omics" research efforts into improved and individualized health care in DKD.