Mast cells decrease renal fibrosis in unilateral ureteral obstruction

Kim, Duk Hoon,Moon, Sang-Ok,Jung, Yu Jin,Lee, Ae Sin,Kang, Kyung Pyo,Lee, Tae Hwan,Lee, Sik,Chai, Ok Hee,Song, Chang Ho,Jang, Kyu Yun,Sung, Mi Jeong,Zhang, Xin,Park, Sung Kwang,Kim, Won International Society of Nephrology 2009 Kidney international Vol.75 No.10

Mast cells regulate both inflammatory responses and tissue repair in human diseases but there are conflicting reports on the role of these cells in the pathogenesis of various kidney diseases. Here we measured mast cell function in unilateral ureteral obstruction, a well-characterized model of renal fibrosis, using Kit<SUP>W</SUP>/Kit<SUP>W−v</SUP> mice genetically deficient in mast cells, wild-type mice, and deficient mice reconstituted by adoptive transfer with mast cells from the wild-type animals. Mast cell-deficient mice had higher levels of renal tubular damage, more stromal fibrosis, higher numbers of infiltrating ERHR3-positive macrophages and CD3-positive T cells, and higher tissue levels of profibrotic transforming growth factor-β1 than wild-type mice or mice reconstituted by adoptive transfer of mast cells 3 weeks after ureteral obstruction. Similarly, while wild-type and adoptively transferred mice had increased α-smooth muscle actin and decreased E-cadherin expression, which are indicators of epithelial-mesenchymal transition, the obstructed kidneys of the mast cell–deficient mice had significant attenuation of those indicators. Thus, our study suggests that mast cells protect the kidney against fibrosis by modulation of inflammatory cell infiltration and by transforming growth factor-β1-driven epithelial-to-mesenchymal transitions.Kidney International (2009) 75, 1031–1038; doi:10.1038/ki.2009.1; published online 25 February 2009

Activation of the renin–angiotensin system within podocytes in diabetes

Yoo, T-H,Li, J-J,Kim, J-J,Jung, D-S,Kwak, S-J,Ryu, D-R,Choi, H Y,Kim, J S,Kim, H J,Han, S H,Lee, J E,Han, D S,Kang, S-W International Society of Nephrology 2007 Kidney international Vol.71 No.10

The autocrine and paracrine activation of the renin–angiotensin system (RAS) within cells of the kidney plays a role in the overall pathophysiology of the renal disease due to diabetes. In this study, we focus on components of the RAS in the podocyte as these cells are important in the pathogenesis of glomerulosclerosis and proteinuria. Immortalized mouse podocytes were exposed to media containing normal glucose (NG) or high glucose (HG) for in vitro studies. In vivo studies utilized kidney tissue obtained from rats treated for 3 months with streptozotocin to induce diabetes. Angiotensinogen (AGT) and the angiotensin II (AII) type 1 receptor mRNA and protein were significantly increased in the podocytes cultured under the high glucose conditions. Both angiotensins I and II levels were significantly higher in cell lysates and the conditioned media of cells grown in high glucose. There were no differences in renin activity, angiotensin-converting enzyme level, or AII type 2 receptor level. Glomerular AGT and AII type 1 receptor assessed by means of immunohistochemistry were increased in diabetic rats compared with the control rats. Other measured components of the RAS within the glomeruli were not different. We suggest that increased AGT, an attendant increase in AII and increased AII type 1 receptor in podocytes experiencing diabetic conditions play an important role in the pathogenesis of diabetic nephropathy.Kidney International (2007) 71, 1019–1027. doi:10.1038/sj.ki.5002195; published online 14 March 2007

Retrocaval ureter

Lee, S,Kim, W,Jeong, H J,Sohn, M H,Kim, Y G,Park, S K International Society of Nephrology 2006 Kidney international Vol.70 No.4

Oxidative stress during peritoneal dialysis: Implications in functional and structural changes in the membrane

Noh, H,Kim, J S,Han, K-H,Lee, G T,Song, J S,Chung, S H,Jeon, J S,Ha, H,Lee, H B International Society of Nephrology 2006 Kidney international Vol.69 No.11

Progressive peritoneal fibrosis, membrane hyperpermeability, and ultrafiltration failure have been observed in patients on long-term peritoneal dialysis (PD). The present study tested the hypothesis that reactive oxygen species (ROS) generated by conventional PD solution (PDS) mediate functional and structural alterations of peritoneal membrane in vivo. Sprague–Dawley rats were randomized to control, PDS, PDS with an antioxidant, and PDS with an angiotensin II (Ang II) receptor blocker. Commercial PDS containing 3.86% glucose (20–30 ml) with or without N-acetylcystein (NAC) 10 mM or losartan 5 mg/kg was administered intraperitoneally twice a day for 12 weeks. Control rats received sham injection. Rats treated with PDS had significantly lower drain volume and D<SUB>4</SUB>/D<SUB>0</SUB> glucose, but higher D<SUB>4</SUB>/P<SUB>4</SUB> creatinine and increased membrane thickness and endothelial NOS (eNOS) expression compared to control rats. Omental transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), collagen I, and heat-shock protein (hsp) 47 expression and lipid peroxide levels and dialysate VEGF and Ang II concentrations were significantly increased in rats treated with PDS compared to control. All of these changes were prevented by both NAC and losartan. In conclusion, the present study demonstrates that ROS generated by conventional PDS are, in large part, responsible for peritoneal fibrosis and membrane hyperpermeability. We suggest that antioxidants or Ang II receptor blockers may allow better preservation of the structural and functional integrity of the peritoneal membrane during long-term PD.Kidney International (2006) 69, 2022–2028. doi:10.1038/sj.ki.5001506; published online 26 April 2006

CD4⁺CD25⁺ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice

Lee, Hyojung,Nho, Dukhee,Chung, Hwan-Suck,Lee, Heekyung,Shin, Min-Kyu,Kim, Sung-Hoon,Bae, Hyunsu International Society of Nephrology 2010 Kidney international Vol.78 No.11

Nephrotoxicity limits the use of cisplatin, a widely used chemotherapeutic agent for treatment of various malignancies. Overall, CD4<SUP>+</SUP> T cells mediate cisplatin-induced renal injury; however, the CD4<SUP>+</SUP>CD25<SUP>+</SUP> regulatory T-cell subset (CD4<SUP>+</SUP>CD25<SUP>+</SUP> Treg) has broad suppressive effects on many different cell types. In this study, we determined whether CD4<SUP>+</SUP>CD25<SUP>+</SUP> Treg cells had protective effects against cisplatin-induced acute renal injury in nu/nu mice that lack mature T cells. In these mice, there was marked attenuation of the decreased survival, renal dysfunction and tubular injury, renal tumor necrosis factor-α, and interleukin-1β cytokine levels. Furthermore, renal macrophage accumulation was reduced in CD4<SUP>+</SUP>CD25<SUP>+</SUP> Treg cell-adoptive transferred nu/nu mice compared with control mice. Infusion of CD4<SUP>+</SUP>CD25<SUP>+</SUP>Treg cells into wild-type Balb/c mice reduced serum blood urea nitrogen and creatinine levels equivalent to those in nu/nu mice and extended their survival time after cisplatin injection. In contrast, depletion of CD4<SUP>+</SUP>CD25<SUP>+</SUP> Treg cells in wild-type mice exacerbated kidney injury after cisplatin administration. Transcription factor Foxp3-positive cells (Treg cells) were detected in the kidneys of nu/nu mice after cisplatin injection. Our results suggest that CD4<SUP>+</SUP>CD25<SUP>+</SUP> Treg cells directly affect cisplatin nephrotoxicity and their modulation represents an additional treatment strategy.

IN-1130, a novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy

Moon, J-A,Kim, H-T,Cho, I-S,Sheen, Y Y,Kim, D-K International Society of Nephrology 2006 Kidney international Vol.70 No.7

The transforming growth factor-β (TGF-β) plays a central role in the progression of renal fibrosis. TGF-β transduces its signal through the activin receptor-like kinase (ALK)5. IN-1130, a novel small molecule ALK5 inhibitor, inhibited the purified kinase domain of ALK5-mediated Smad3 phosphorylation with an IC<SUB>50</SUB> value of 5.3 nM. IN-1130 proved to be highly selective in a panel of 27 serine/threonine and tyrosine kinases including p38α mitogen-activated protein kinase. We evaluated the efficacy of IN-1130 to block renal fibrogenesis induced by unilateral ureteral obstruction (UUO) in rats. Either vehicle (saline) or IN-1130 (10 and 20 mg/kg/day) was intraperitoneally administered to UUO rats for 7 and 14 days. Phosphorylated Smad2 (pSmad2) and markers of fibrosis were analyzed in kidney tissues. In UUO control kidneys, interstitial fibrosis including tubular atrophy, loss and dilation, inflammatory cell infiltration, and fibroblast cell proliferation was prominent. These morphological changes were notably reduced by IN-1130 treatment. IN-1130 decreased levels of TGF-β1 messenger RNA (mRNA), type I collagen mRNA, and pSmad2, compared to UUO control rats. As determined by measuring the hydroxyproline content, total kidney collagen amount was increased in UUO control kidneys, but significantly reduced by IN-1130 treatment, which was comparable to results of histochemical staining for collagen. IN-1130 also suppressed the expression of α-smooth muscle actin (α-SMA) and fibronectin in UUO kidneys. Our results show that IN-1130 suppressed the fibrogenic process of UUO, further underscoring the potential clinical benefits of IN-1130 in the treatment of renal fibrosis.Kidney International (2006) 70, 1234–1243. doi:10.1038/sj.ki.5001775; published online 23 August 2006

Regulatory mechanisms of Na⁺/glucose cotransporters in renal proximal tubule cells

Lee, Y J,Lee, Y J,Han, H J International Society of Nephrology 2007 Kidney international Vol.72 No.suppl106

Glucose is a key fuel and an important metabolic substrate in mammals. Renal proximal tubular cells (PTCs) not only reabsorb filtered glucose but are also believed to play a role in the glucotoxicity associated with renal pathogenesis, such as in diabetes. The proximal tubule environment is where 90% of the filtered glucose is reabsorbed by the low-affinity/high-capacity Na<SUP>+</SUP>/glucose cotransporter 2 (SGLT2) and facilitated diffusion glucose transporter 2 (GLUT2). Both active and facilitative glucose transporters have distinct distribution profiles along the proximal tubule related to their particular kinetic characteristics. A number of mechanisms contribute to the changes in the cellular functions, which occur in response to exposure to various endogenous factors. Hyperglycemia was reported to regulate the renal SGLT activities through the reactive oxygen species–nuclear factor-κB pathways, which suggests that the transcellular glucose uptake within the PTCs contribute to the development of diabetic-like nephropathy. Angiotensin II (ANG II) plays an important role in its development through epidermal growth factor receptor (EGFR) transactivation. Therefore, a combination of high glucose, ANG II, and EGF are involved in diabetic-like nephropathy by regulating the SGLT activity. In addition, endogenously enhanced SGLTs have a cytoprotective function. The renal proximal tubules play a major role in regulating the plasma glucose levels, and there is increasing interest in the renal glucose transporters on account of their potential implications in the treatment of various conditions including diabetes mellitus.Kidney International (2007) 72, S27–S35. doi:10.1038/sj.ki.5002383

Histone deacetylase inhibitors: A novel class of therapeutic agents in diabetic nephropathy

Lee, H B,Noh, H,Seo, J Y,Yu, M R,Ha, H International Society of Nephrology 2007 Kidney international Vol.72 No.suppl106

Histone deacetylase (HDAC) inhibitors are currently being tested as anticancer agents in clinical trials. Chromatin remodeling, such as through histone acetylation, is a fundamental phenomenon in eukaryotic cell biology, bearing implications to numerous physiological and pathological phenomena. Here, we discuss recent data from our own laboratory and those of others demonstrating antifibrotic and renoprotective effect of HDAC inhibitors in diabetic kidneys, and the possible mechanisms including the role of reactive oxygen species. HDAC inhibitors may prove to be a novel class of multitarget agents in the treatment of diabetic nephropathy.Kidney International (2007) 72, S61–S66. doi:10.1038/sj.ki.5002388

Genistein protects the kidney from cisplatin-induced injury

Sung, Mi Jeong,Kim, Duk Hoon,Jung, Yu Jin,Kang, Kyung Pyo,Lee, Ae Sin,Lee, Sik,Kim, Won,Davaatseren, Munkhtugs,Hwang, Jin-Taek,Kim, Hyun-Jin,Kim, Myung Sunny,Kwon, Dae Young,Park, Sung Kwang International Society of Nephrology 2008 Kidney international Vol.74 No.12

Oxidative stress and inflammation contribute to the pathogenesis of cisplatin-induced nephrotoxicity. We found that genistein, a tyrosine kinase inhibitor with broad specificities, and which also has estrogen-like activity, had protective effects on cisplatin-induced renal injury in mice. Genistein significantly decreased reactive oxygen species production, the expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 proteins, as well as the translocation of the p65 subunit of nuclear factor-κB into the nucleus and the infiltration of macrophages, all of which were increased in the kidney by cisplatin treatment. Genistein also decreased cisplatin-induced apoptosis by regulating p53 induction in kidney. Genistein significantly reduced reactive oxygen species production in cisplatin-treated normal human kidney HK-2 cells. These studies show that genistein or similar compounds might be useful in prevention of cisplatin-induced renal injury.Kidney International (2008) 74, 1538–1547; doi:10.1038/ki.2008.409; published online 20 August 2008

Iodixanol vs ioxaglate for preventing contrast nephropathy: Who is winner ?

Jo, S-H,Koo, B-K,Youn, T-J,Kim, H-S International Society of Nephrology 2007 Kidney international Vol.71 No.8