The apoptotic program promotes
tissue remodeling and fibrosis
To the Editor: Havasi and Borkan1
observations that link apoptosis to cell deletion and loss of
organ function after acute kidney injury. Although the major
consequence of apoptosis is cell death, emerging evidence
suggests that apoptosis is involved in tissue remodeling and
The molecular machinery regulating the effector phase of
apoptosis favors the extracellular translocation of a highly
regulated set of mediators of importance in leukocyte
trafficking and tissue remodeling. This molecular legacy
mounts a communication network with surrounding cells to
tissue repair in a paracrine manner, which is of importance in
the setting of kidney injury.2
including fractalkine, monocyte chemoattractant protein 1,
and lysophosphatidylcholine, to promote the recruitment
of macrophages and monocytes at the site of apoptosis.2
Apoptotic cells produce profibrogenic cytokines, including
epidermal growth factor, and their engulfment by phagocytes
promotes transforming growth factor-b secretion. Caspase-3
activation in apoptotic endothelial cells triggers the export of
connective tissue growth factor, which in turn functions as a
necessary co-factor of myofibroblast differentiation.3Caspase-3
activation also leads to the externalization of cathepsin L,
which in turn cleaves the extracellular matrix component
perlecan generating a truncated C terminal fragment (LG3)
that activates prosurvival pathways in fibroblasts and vascular
smooth muscle cells.4
In conclusion, apoptosis should be viewed not only as a
cell-deletion pathway but also as a biological process that
engages intercellular crosstalks of central importance in tissue
remodeling and repair.
1. Havasi A, Borkan SC. Apoptosis and acute kidney injury. Kidney Int 2011;
Cailhier JF, Laplante P, Hebert MJ. Endothelial apoptosis and chronic
transplant vasculopathy: recent results, novel mechanisms.
Am J Transplant 2006; 6: 247–253.
Laplante P, Sirois I, Raymond MA et al. Caspase-3-mediated secretion of
connective tissue growth factor by apoptotic endothelial cells promotes
fibrosis. Cell Death Differ 2010; 17: 291–303.
Laplante P, Raymond MA, Labelle A et al. Perlecan proteolysis induces an
alpha2beta1 integrin- and Src family kinase-dependent anti-apoptotic
pathway in fibroblasts in the absence of focal adhesion kinase activation.
J Biol Chem 2006; 281: 30383–30392.
Nicolas Pallet1and Marie-Jose ´e He ´bert1
1Centre de Recherche de l’Ho ˆpital Notre Dame, Centre Hospitalier de
l’Universite ´ de Montre ´al (CRCHUM), Montreal, Quebec, Canada
Correspondence: Marie-Jose ´e He ´bert, Centre de Recherche de l’Ho ˆpital
Notre Dame, Centre Hospitalier de l’Universite ´ de Montreal, 1560 Rue
Sherbrooke East, Montre ´al, Quebec, Canada H2L 4M1.
Kidney International (2011) 80, 1108; doi:10.1038/ki.2011.307
The Authors reply: In their letter, Pallet and He ´bert1
astutely observe that renal cell injury including apoptosis
potentially aggravates renal fibrosis, inflammation, and
chronic organ injury. The specific messengers that precipitate
fibrosis and alterations in extracellular matrix proteins are
debated and include chemotactic factors, profibrogenic
cytokines such as epidermal growth factor and transforming
growth factor b, proinflammatory caspases, and cathepsin. In
addition, it is now accepted that acute kidney injury often
leaves subtle tubular and vascular defects associated with
renal fibrosis and increases the risk of end-stage renal
disease.2,3In addition to the above ‘messengers of injury’,
recent evidence suggests that many cell types are capable of
releasing microvesicles containing both RNA and DNA that
induce signals in other cell types and even in distant tissues in
a paracrine/endocrine fashion.4Although we focused on the
acute consequences of renal cell injury and apoptosis in our
review,5Pallet and He ´bert’s letter identifies a key research
area, namely, the biological relationship between acute and
chronic kidney injury and the propensity of acute renal
injury to precipitate damage in other organs. Given the
recent appreciation that acute injury begets chronic organ
disease,6it is essential that we identify the profibrotic
messengers and their targets to interrupt an epidemic of
1.Pallet N, He ´bert M-J. The apoptotic program promotes tissue remodeling
and fibrosis. Kidney Int 2011; 80: 1108.
Swaminathan S, Shah SV. Novel inflammatory mechanisms of accelerated
atherosclerosis in kidney disease. Kidney Int 2011; 80: 453–463.
Pannu N, James M, Hemmelgarn BR, Dong J et al. Modification of
outcomes after acute kidney injury by the presence of CKD.
Am J Kidney Dis 2011; 58: 206–213.
Reich III CF, Pisetsky DS. The content of DNA and RNA in microparticles
released by Jurkat and HL-60 cells undergoing in vitro apoptosis. Exp Cell
Res 2009; 315: 760–768.
Havasi A, Borkan SC. Apoptosis and acute kidney injury. Kidney Int 2011;
Sanoff S, Okusa MD. Impact of acute kidney injury on chronic kidney
disease and its progression. Contrib Nephrol 2010; 171: 213–217.
Andrea Havasi1and Steven C. Borkan2
1Renal Section, Boston University, Boston, Massachusetts, USA and
2Renal Section, Boston Medical Center, Boston, Massachusetts, USA
Correspondence: Steven C. Borkan, Renal Section, Boston Medical Center,
Evan’s Suite 434, 88 East Newton Street, Boston, Massachusetts 02118, USA.
Kidney International (2011) 80, 1108; doi:10.1038/ki.2011.309
Hydrogen sulfide increases after a
single hemodialysis session
To the Editor: Hydrogen sulfide, H2S, the third endogenous
gas with cardiovascular properties after nitric oxide and
carbon monoxide, is a newly recognized vasorelaxant, and
H2S deficiency is involved in the pathogenesis of hypertension
Kidney International (2011) 80, 1107–1109
letter to the editor