| Authors |
Zhang H, Nair V, Saha J, Atkins KB, Hodgin JB, Saunders TL, Myers MG, Werner T,
Kretzler M, Brosius FC
|
| Submitted By |
Jeffrey Hodgin on 6/5/2017 |
| Status |
Published |
| Journal |
Kidney international |
| Year |
2017 |
| Date Published |
|
| Volume : Pages |
Not Specified : Not Specified |
| PubMed Reference |
28554737 |
| 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.
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