This study was conducted to test the hypothesis that, during renal development, the Na-K-2Cl cotransporter type 2 (NKCC2) activates the tonicity-responsive enhancer binding protein (TonEBP) transcription factor by creating medullary hypertonicity. TonEBP, in turn, drives the expression of aldose reductase (AR) and urea transporter-A (UT-A). Kidneys from 13- to19-day-old fetuses ( F13– F19), 1- to 21-day-old pups ( P1– P21), and adult mice were examined by immunohistochemistry. NKCC2 was first detected on F14 in differentiating macula densa and thick ascending limb (TAL). TonEBP was first detected on F15 in the medullary collecting duct (MCD) and surrounding endothelial cells. AR was detected in the MCD cells of the renal medulla from F15. UT-A first appeared in the descending thin limb (DTL) on F16 and in the MCD on F18. After birth, NKCC2-positive TALs disappeared gradually from the tip of the renal papilla, becoming completely undetectable in the inner medulla on P21. TonEBP shifted from the cytoplasm to the nucleus in both vascular endothelial cells and MCD cells on P1, and its abundance increased gradually afterward. Immunoreactivity for AR and UT-A in the renal medulla increased markedly after birth. Treatment of neonatal animals with furosemide dramatically reduced expression of TonEBP, AR, and UT-A1. Furosemide also prevented the disappearance of NKCC2-expressing TALs in the papilla. The sequential expression of NKCC2, TonEBP, and its targets AR and UT-A and the reduced expression TonEBP and its targets in response to furosemide treatment support the hypothesis that local hypertonicity produced by the activity of NKCC2 activates TonEBP during development.

Thus, infiltrating macrophages were involved in both nonimmunologic and immunologic injury and led to apoptotic cell death in this rat model of chronic CsA nephropathy.

The CD4+CD25+ T regulatory cells (Tregs) play an important role in immune tolerance in experimental transplantation but the clinical significance of circulating Tregs in the peripheral blood is undetermined. In 50 kidney transplant (KT) recipients, 29 healthy controls and 32 liver transplant (LT) recipients, the frequency of Tregs was measured with flow cytometry before and after transplantation. In the KT recipients, IL-10 secretion was measured with an enzyme-linked immunospot (ELISPOT) assay. The median frequency of circulating Tregs before KT was similar to that in healthy controls but significantly lower than that in LT patients before transplantation. The frequency of Tregs was significantly decreased in patients with subclinical acute rejection compared with those without subclinical acute rejection. Calcineurin inhibitors (CNIs) and anti-CD25 antibody decreased the frequency of Tregs but mTOR inhibitor did not. The frequency of donor-specific IL-10 secreting cells did not correlate with the number of Tregs. The frequency of circulating Tregs in KT recipients is strongly affected by CNIs and anti-CD25 antibody, and a low frequency of Tregs is associated with subclinical acute rejection during the early posttransplant period.

Pendrin is an apical anion exchanger found in type B and nonA-nonB intercalated cells that is involved in bicarbonate secretion. The purpose of this study was to establish the origin and fate of pendrinpositive intercalated cells in the mouse kidney. Using immunohistochemistry, we found that pendrinpositive cells first appeared in the connecting tubule at embryonic day 14 (E14) and subsequently in the medullary collecting duct at E18. Most of the pendrin-positive cells in the connecting tubule were nonA-nonB intercalated cells, wheras those in the medullary collecting duct were type B intercalated cells. In the cortical collecting duct, pendrin-positive cells appeared in the inner part at day 4 after birth and in the outer part at day 7. Pendrin-positive cells gradually disappeared by apoptosis from the inner part of the medullary collecting duct two weeks after birth. Using 5-bromo-2Јdeoxy-uridine (BrdU) to follow cell proliferation, we determined that selective proliferation of pendrin-positive intercalated cells does not occur; instead, these cells may arise from undifferentiated precursor cells from separate foci, one in the connecting tubule and one in the collecting duct.

D-tyrosine is known to negatively regulate melanin synthesis by inhibiting tyrosinase activity. Here, we further reveal that peptides containing terminal D-tyrosine can reduce the melanin contents of human melanocytes. the addition of D-tyrosine to the terminus of the commercial anti-wrinkle peptide, pentapeptide-18 endowed the peptide with the ability to reduce the melanin content and tyrosinase activity in human MNT-1 melanoma cells and primary melanocytes. Consistently, terminal D-tyrosine-containing pentapeptide-18 inhibited the melanogenesis induced by α-MSH treatment or UV irradiation of MNT-1 cells and reduced melanin synthesis in the epidermal basal layer of a 3D human skin model. Furthermore, the addition of D-tyrosine to an anti-aging peptide (GEKG) or an antiinflammatory peptide (GHK) endowed these short peptides with anti-melanogenic effects without altering their intrinsic effects. Together, these data suggest that the addition of D-tyrosine at the terminus of a short cosmetic peptide adds an anti-melanogenic effect to its intrinsic cosmetic effect. Our work offers a novel means of generating dual-function cosmetic peptides.Melanin synthesis occurs in melanocytes and is an essential physiological process that determines the color of human skin and protects its DNA from UV damage 1 . It is closely related with the occurrence of pigmentary disorders 2 : the imbalanced regulation of melanin synthesis results in many pigmentary skin diseases that commonly affect men and women of all ethnic groups 3 , including hyperpigmentation disorders, such as melanocytic nevus, seborrheic keratosis, and melanoma, and hypopigmentation disorders, such as piebaldism, pityriasis, and vitiligo.Melanin is synthesized in melanosomes, which are transferred to surrounding keratinocytes where they protect cells against DNA damage 4,5 . Melanogenesis is critically regulated by the expression of various melanogenesis-related enzymes, such as tyrosinase, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2). Tyrosinase, the rate-limiting enzyme for controlling melanin synthesis, is involved primarily in the production of L-dopaquinone 5,6 . TRP-1 and TRP-2 catalyze specific steps in melanogenesis and stabilize tyrosinase activity 7 . As tyrosinase is a key enzyme that catalyzes a rate-limiting step of melanin synthesis, numerous inhibitors that target tyrosinase have been investigated for their ability to inhibit this process. These include well-known tyrosinase inhibitors, such as hydroquinone 8 , arbutin 9 , kojic acid 10 , and salicylic acid 11 . However, due to the side effects of these inhibitors and the increasing demand for safe and effective cosmetics, many continuing efforts are being made to identify or produce new skin-whitening agents. Some researchers have screened natural products and found that chalcones, resveratrol, and coumarins exhibit inhibitory activity against mushroom tyrosinase 12 . Other groups have sought to develop bioactive materials. Particular attention has been paid to vario...

We previously reported that syndecan‐2 expression is increased on the colonic epithelium during chronic inflammation. Here, we report that syndecan‐2 exhibits a different pattern of site‐specific colonic expression during acute inflammation. Syndecan‐2 expression was up‐regulated predominantly in the proximal colon of dextran sulfate sodium‐induced colitis mice. The colitis‐associated up‐regulation of syndecan‐2 was barely detected in Rag‐1−/− (recombination activating gene 1 knockout) mice under colitis‐inducing conditions. Increased syndecan‐2 expression correlated with increased levels of infiltrated CD4+IL‐17A+ T cells in the proximal colon. Serum levels of IL‐17A were increased during the acute inflammatory response in normal mice but not Rag‐1−/− mice. IL‐17A directly induced IL‐17 receptor (IL‐17RA) and syndecan‐2 expression in ex vivo‐cultured proximal colon tissues and adenoma cell lines from proximal colon. IL‐17RA knockdown reduced the IL‐17A‐mediated syndecan‐2 expression in SNU1235 cells. No elevation of syndecan‐2 or IL‐17RA was observed in colonic tissues from IL‐17A−/− mice during colitis induction. Finally, increased expression of syndecan‐2 and IL‐17RA was observed in the proximal colons of cecal ligation and puncture‐induced sepsis mice and infectious pan colitis patients. Together, these data suggest that acute inflammation induces syndecan‐2 expression predominantly in the proximal colon via IL‐17A‐IL‐17RA signaling during the early stage of the inflammatory response and that proximal colonic syndecan‐2 might be a biomarker for acute inflammation.—Hong, H., Song, H.‐K., Hwang, E. S., Lee, A. R., Han, D. S., Kim, S.‐E., Oh, E.‐S. Up‐regulation of syndecan‐2 in proximal colon correlates with acute inflammation. FASEB J. 33, 11381–11395 (2019). http://www.fasebj.org

CsA-induced renal injury recruits nestin-expressing cells to injured areas, and these cells might be involved in reparative fibrosis in the progression of chronic CsA nephropathy.

These findings suggest that upregulation of HA and its binding receptors are involved in interstitial fibrosis in chronic CsA-induced renal injury.