pathology-2018-scientifictracks

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Pathology 2018 Research & Reviews: Journal of Medical and Health Sciences
ISSN: 2319-9865 Page 43
October 08-09, 2018
Edinburgh, Scotland
17th International Conference on
Pathology & Cancer
Epidemiology
T his presentation highlights results from author’s laboratory
in the role of endothelin-1 (ET-1) signaling in damaging renal
proximal tubules in proteinuric kidney disease, renal carcinoma
and tubulotoxicity, involving miRNAs. MicroRNAs (miRNAs)
are short non-coding RNAs that can play important roles in cell
function and development by targeting mRNA sequences of
protein-coding transcripts, resulting in either mRNA cleavage
or repression of productive translation. Inflammation/Tumor:
Author’s research groups has demonstrated that ET-1 plays a
major role as a mediator of cellular signaling in primary renal
proximal tubule cells, which express both its receptor subtypes
(A, B). Inproteinuricdiseasessuchasmembranousnephropathy
or focal segmental sclerosis leading to inflammation and
subsequent fibrosis as well as in tubular carcinoma cells
(CAKI-1), ET-1 is able to activate a cytoplasmic transcription
complex consisting of NF-κB p65, MAPK p38α, and PKCα.
Consequently, PKCα is no longer able to transmigrate in the
nucleus, which leads to loss of suppression of a primiRNA15a,
maturation of this miRNA in the cytoplasm, its tubular secretion
and detectability in the urine. This mechanism seems to exist in
minimal change disease, membranous nephropathy and focal
segmental sclerosis. Upregulating PKCα levels in vitro and in
an Adriamycin model of proteinuria results in undetectable
levels of miRNA15a in the urine. This may lend itself as
marker controlling the effect of therapy and compliance. In
renal tumors, high miRNA15a levels (and respective low PKCα
levels) are characteristic for malignant clear cell carcinoma
being inversely correlated in benign oncocytoma. Tumor
resection results in background urinary miRNa15a levels.
Meanwhile, the NF-κB p65 has unrestricted nuclear access,
transcribing NF-κB responsive genes. Proliferation/Tumor
suppression: miRNa15a induces a splice-form of MAPK p38α,
called Mxi-2. We showed that Mxi-2 is a transcription factor in
proximal tumor cells. Building a complex with ETS-1 and ERK,
it activates p16/p21. Furthermore, in a RISC (RNA-induced
silencing complex) in the cytoplasm together with Ago2 and
miRNA1285 it blocks nuclear transmigration of p53, indicating
a potential block of tumor suppression. Tubulotoxicity:
Through evolution, the regulatory induction of the multiple drug
resistant protein 2 (MRP2) via ET-1 receptor B (ETBR) is known.
We showed that in an Adriamycin model as well as in human
biopsies of proteinuric disease, MRP2 is downregulated. This
regulation occurs via ET-1 stimulation of ETBR and activation
of miRNA133a, interacting with the 3’UTR region of the MRP2
gene. The excretion of this miRNA could be used as surrogate
marker for MRP2 downregulation. This mechanism is also
explains tubulotoxicity in renal transplant patients treated with
cyclosporine A (CyA): MRP2 responsible for tubular excretion
is downregulated in CyA tubulotoxic damage as shown by
quantitative immune histology of MRP2 vs. controls (CyA-
arteriolopathy, CyA non-affected transplants, and normal
kidneys). miRNAs could be useful as (i) biomarkers in the
urine for renal carcinoma; (ii) indicators of activated signaling
pathways in proteinuric disease; (iii) as surrogate marker for
potential tubulotoxicity, particularly when tubulotoxic drugs
like CyA are considered as treatment in proteinuric diseases
such as pediatric FSGS.
Biography
Prof. Dr. Jochen Fries is the head of a translational pathology laboratory,
University Hospital of Cologne, Germany, focusing on the role of endo-
thelin-1, its signal transduction and the function of its newly defined tar-
get genes in renal and urogenital pathology. He has published more than
60 research paper in various international journals in the field of Chronic
Renal Disease, Cardiac Disease / Vascular Disease, Molecular Therapy
/ Transplantation Technology/ Stem Cell Technology. He was trained in
Surgical Pathology at the Brigham and Women’s Hospital and obtained
postdoctoral training from the Brigham and Women’s Hospital, Children’s
Hospital, and Harvard School of Public Health in Boston.
Endothelin-1 signaling in diseases damaging the renal
proximal tubule: protein uric kidney disease–renal
carcinoma–tubulotoxicity – diagnostic approaches and
therapeutic considerations
Jochen W U Fries
University Hospital of Cologne, Germany
Jochen W U Fries, RRJMHS 2018
Volume: 7