The formation of kidney local microenvironment after acute kidney injury. - PROJECT SUMMARY/ABSTRACT
Acute kidney injury (AKI) is characterized by abrupt deterioration in kidney function, manifested by an increase
in serum creatinine level, with or without a reduction in the amount of urine output. In the US, there was close
to one million AKI hospitalizations in 2000, and this number quadrupled by 2014. The morbidity, mortality, and
costs of AKI are far greater than formerly acknowledged. Regardless of the initial causes of AKI, renal tubules
are considered to be the epicenter of damage. Little attention is paid to the changes of the renal local
microenvironment in AKI, although the concept of a ‘microenvironment’ has already shaped our understanding
of the pathogenesis of various diseases. The kidney microenvironment in AKI is comprised of different cellular
components such as injured tubular cells, activated fibroblasts, extracellular matrix (ECM), and a variety of
secreted factors. In general, after AKI, renal tubules undergo a repair process of dedifferentiation. During this
process, ECM is an indispensable component in organizing a favorable microenvironment to promote tubule
repopulation. To further understand the role of ECM in the formation of the kidney microenvironment, we
constructed an ischemic kidney injury model at 10 different time points, from day 0 to 10. By using proteomics,
we found that extracellular matrix protein 1 (ECM1) was the earliest activated matrix protein after ischemic AKI.
We then experimentally confirmed that ECM1 was induced rapidly, as early as 4-8h after AKI, and it
predominantly localizes at the foci rich in fibroblasts. In the kidney, the fibroblast is the major cellular resource
of ECM synthesis. The data generated by my K01 award revealed that, in AKI, fibroblast activation is a
superior early event, and it occurs far earlier than tubular cell proliferation. Meanwhile, a tubule-derived novel
growth factor, Sonic Hedgehog (Shh) was secreted by renal tubules and specifically targets fibroblasts. By
immunoprecipitation, we found that ECM1 can bind to the Shh ligand in vitro. Based on these findings, we
hypothesized that after AKI, ECM1 directly recruits Shh to form a favorable microenvironment to
promote kidney remodeling.We will test this hypothesis in two specific aims: 1) Determine the mechanistic
role of ECM1 in microenvironment formation ex vivo. 2) Determine the role of the ECM1-organized
microenvironment in promoting AKI repair in vivo. The data generated from this application will have wide
implications in comprehending the pathogenesis of kidney repair and in designing novel therapeutic regimens
for AKI treatment.
