The single-cell transcriptomic landscape of early human diabetic nephropathy

Parker C. Wilson, Haojia Wu, Yuhei Kirita, Kohei Uchimura, Nicolas Ledru, Helmut G. Rennke, Paul A. Welling, Sushrut S. Waikar, Benjamin D. Humphreys

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single-nucleus RNA sequencing (snRNA-seq) on cryopreserved human diabetic kidney samples to generate 23,980 single-nucleus transcriptomes from 3 control and 3 early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side-by-side comparison demonstrated cell-type-specific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic thick ascending limb, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na+/K+-ATPase, WNK1, mineralocorticoid receptor, and NEDD4L expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule, and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy.

Original languageEnglish
Pages (from-to)19619-19625
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number39
DOIs
StatePublished - Sep 24 2019

Keywords

  • Diabetic nephropathy
  • RNA-seq
  • Single cell

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