CDCP1 promotes compensatory renal growth by integrating Src and Met signaling

Compensatory growth of organs after loss of their mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that CUB domain-containing protein 1 (CDCP1) promotes HGF-induced compensatory renal growth. Using canine kidney cells as a model of renal tubules, we found that HGF-induced temporal up-regulation of Src activity and its scaffold protein, CDCP1, and that the ablation of CDCP1 robustly abrogated HGF-induced phenotypic changes, such as morphological changes and cell growth/proliferation. Mechanistic analyses revealed that up-regulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, and activated STAT3 induces the expression of matrix metalloproteinases and mitogenic factors. After unilateral nephrectomy in mice, the Met-STAT3 signaling is transiently up-regulated in the renal tubules of the remaining kidney, whereas CDCP1 ablation attenuates regenerative signaling and significantly suppresses compensatory growth. These findings demonstrate that CDCP1 plays a crucial role in controlling compensatory renal growth by focally and temporally integrating Src and Met signaling.

Compensation Capacity of The Living-Related Donor’s Remnant Kidney and Recipient’s Transplanted Kidney

Background: Compensatory renal growth following nephrectomy is common. We try to explore the compensatory capacity of the living-related donor’s remnant kidney and recipient’s transplanted kidney in terms of the glomerular filtration rate (GFR) one month after transplantation. Methods: Clinical data of 94 patients who received living-related kidney transplantation in our hospital between June 2007 and December 2017 were reviewed retrospectively. GFR was calculated by 99mTc-DTPA detection. The GFR compensatory capacity of donor’s remnant and donated kidneys in their new milieus after transplantation was compared. The differential value (D-value) of split renal function was defined as postoperative GFR - preoperative ipsilateral GFR. The compensatory percentage (C-percentage) of split renal function was defined as (postoperative GFR - preoperative ipsilateral GFR)/preoperative ipsilateral GFR. Results: The median D-value of the donor’s remnant kidney increased by 20.8 ml/(min·1.73m2)[IQR=8.9-29.6 ml/(min·1.73m2)] with a C-percentage of 46.6% (IQR=17.0%-73.0%). The median D-value of the donated kidney increased by 30.6 ml/(min·1.73m2)[IQR=19.8-42.3 ml/(min·1.73m2)] with a C-percentage of 67.8% (IQR=39.6%-94.7%). Multivariable analysis showed that only split preoperative GFR in the donor was the independent predictor for C-percentage of the split kidney. Conclusions: Renal function could be well preserved and compensated after kidney donation in most donors and recipients in Chinese population. Healthy donors with a good GFR before operation possessed a mighty functional compensation capacity.

CUB domain-containing protein 1 controls HGF responses by integrating Src and Met–STAT3 signaling

Hepatocyte growth factor (HGF) controls various biological responses, including morphogenesis, organ regeneration, and cancer invasion, by activating its receptor, Met. However, the mechanisms that precisely control diverse Met signaling remain unclear. Here, we identified CUB domain-containing protein 1 (CDCP1) as a crucial element of HGF signaling. In MDCK cysts, HGF induced Src activation via CDCP1 upregulation, and CDCP1 ablation abrogated HGF responses, i.e., extended invasive cell protrusions and promoted cell growth/proliferation. Mechanistically, CDCP1 upregulation promoted Src recruitment into lipid rafts to activate Met-associated STAT3. In breast cancer cells in which Met and CDCP1 were co-upregulated, CDCP1 knockdown suppressed HGF-induced cell invasion. Furthermore, in vivo analysis showed that CDCP1 ablation suppressed compensatory renal growth by attenuating Met–STAT3 signaling. These findings demonstrate that CDCP1 plays a crucial role in controlling HGF responses by integrating Src and Met-STAT3 signaling, and provide new insights into the regulatory mechanisms underlying the multifaceted functions of HGF.

Mysterious inhibitory cell regulator investigated and found likely to be secretogranin II related

In the context of a hunt for a postulated hormone that is tissue-mass inhibiting and reproductively associated, there is described probable relatedness to a granin protein. A 7–8 kDa polypeptide candidate (gels/MS) appeared in a bioassay-guided fractionation campaign involving sheep plasma. An N-terminal sequence of 14 amino acids was obtained for the polypeptide by Edman degradation. Bioinformatics and molecular biology failed to illuminate any ovine or non-ovine protein which might relate to this sequence. The N-terminal sequence was synthesized as the 14mer EPL001 peptide and surprisingly found to be inhibitory in an assay in vivo of compensatory renal growth in the rat and modulatory of nematode fecundity, in line with the inhibitory hormone hypothesis. Antibodies were raised to EPL001 and their deployment upheld the hypothesis that the EPL001 amino acid sequence is meaningful and relevant, notwithstanding bioinformatic obscurity. Immunohistochemistry (IHC) in sheep, rodents and humans yielded staining of seeming endocrine relevance (e.g. hypothalamus, gonads and neuroendocrine cells in diverse tissues), with apparent upregulation in certain human tumours (e.g. pheochromocytoma). Discrete IHC staining in Drosophila melanogaster embryo brain was seen in glia and in neuroendocrine cells, with staining likely in the corpus cardiacum. The search for the endogenous antigen involved immunoprecipitation (IP) followed by liquid chromatography and mass spectrometry (LC–MS). Feedstocks were PC12 conditioned medium and aqueous extract of rat hypothalamus—both of which had anti-proliferative and pro-apoptotic effects in an assay in vitro involving rat bone marrow cells, which inhibition was subject to prior immunodepletion with an anti-EPL001 antibody—together with fruit fly embryo material. It is concluded that the mammalian antigen is likely secretogranin II (SgII) related. The originally seen 7–8 kDa polypeptide is suggested to be a new proteoform of secretogranin II of ∼70 residues, SgII-70, with the anti-EPL001 antibody seeing a discontinuous epitope. The fly antigen is probably Q9W2X8 (UniProt), an uncharacterised protein newly disclosed as a granin and provisionally dubbed macrogranin I (MgI). SgII and Q9W2X8 merit further investigation in the context of tissue-mass inhibition.

Effect of benign and tumor parenchyma metabolomic profiles on compensatory renal growth in renal cell carcinoma surgical patients.

446 Background: Pre-operative kidney volume is an independent predictor of glomerular filtration rate in renal cell carcinoma patients. Compensatory renal growth (CRG) can ensue prior to nephrectomy in parallel to tumor growth and benign parenchyma loss. We aimed to test whether renal metabolite abundances significantly associate with CRG, suggesting a causative relationship. Methods: Tissue metabolomics data from 49 patients, with a median age of 60 years, were previously collected and the pre-operative fold-change of their contra to ipsi-lateral benign kidney volume served as a surrogate for their CRG. Contra-lateral kidney volume fold-change within a 3.3 +/- 2.1 years follow-up interval was used as a surrogate for long-term CRG. Using a multivariable statistical model we identified metabolites whose abundances significantly associate with CRG. Results: We identified 13 metabolites in the benign (e.g. L-urobilin) and 163 metabolites in the malignant (e.g. 3-indoxyl-sulfate) tissues to significantly associate with CRG. Benign/tumor fold change in metabolite abundances revealed three additional metabolites with a significant positive association with CRG (e.g. p-cresol sulfate). At the pathway level, we show that fatty-acid oxidation is highly enriched with metabolites whose benign tissue abundances strongly positively associate with CRG, whereas in the tumor tissue significant enrichment of dipeptides (positive association) and benzoate, glycolysis/gluconeogenesis, lysolipid and nucleotide sugar pentose (negative associations) sub-pathways were observed. The effect of metabolite abundances in the benign tissue on long term CRG provided further support for positive association of fatty-acid metabolism sub-pathway enrichment, where sphingolipid, monoacylglycerol, long chain fatty acids, and mid chain fatty acids were enriched for a negative association. Conclusions: These data suggest that specific biological processes in the benign as well as in the tumor parenchyma strongly influence compensatory renal growth.