Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice

Hongyu Zhang, Viji Nair, Jharna Saha, Kevin B. Atkins, Jeffrey B. Hodgin, Thomas L. Saunders, Martin G. Myers, Thomas Werner, Matthias Kretzler, Frank C. Brosius

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Activation of JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease. A 2-3 fold increase in glomerular JAK2 expression, an increase similar to that found in humans with early diabetic kidney disease, led to substantial and statistically significant increases in albuminuria, mesangial expansion, glomerulosclerosis, glomerular fibronectin accumulation, and glomerular basement membrane thickening, and a significant reduction in podocyte density in diabetic mice. Treatment with a specific JAK1/2 inhibitor for 2 weeks partly reversed the major phenotypic changes of diabetic kidney disease and specifically normalized expression of a number of downstream STAT3-dependent genes implicated in diabetic kidney disease progression. Thus, moderate increases in podocyte JAK2 expression at levels similar to those in patients with early diabetic kidney disease can lead directly to phenotypic and other alterations of progressive diabetic glomerulopathy. Hence, inhibition of these changes by treatment with a JAK1/2 inhibitor suggests that such treatment may help retard progression of early diabetic kidney disease in patients.

Original languageEnglish (US)
Pages (from-to)909-921
Number of pages13
JournalKidney International
Volume92
Issue number4
DOIs
StatePublished - Oct 2017
Externally publishedYes

Keywords

  • cell signaling
  • diabetic nephropathy
  • inflammation
  • podocyte

ASJC Scopus subject areas

  • Nephrology

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