A molecular morphometric approach to diabetic kidney disease can link structure
to function and outcome.
Authors Nair V, Komorowsky CV, Weil EJ, Yee B, Hodgin J, Harder JL, Godfrey B, Ju W,
Boustany-Kari CM, Schwarz M, Lemley KV, Nelson PJ, Nelson RG, Kretzler M
Submitted By Jeffrey Hodgin on 11/8/2017
Status Published
Journal Kidney international
Year 2017
Date Published 10/1/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference 29054530
Abstract 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.