Renoprotective Effect of Pioglitazone by the Prevention of Glomerular Hyperfiltration through the Possible Restoration of Altered Macula Densa Signaling in Rats with Type 2 Diabetic Nephropathy

被引:16
作者
Asakura, Juko [1 ]
Hasegawa, Hajime [1 ]
Takayanagi, Kaori [2 ]
Shimazu, Tomokazu [3 ]
Suge, Rie [4 ]
Shimizu, Taisuke [1 ]
Iwashita, Takatsugu [1 ]
Tayama, Yosuke [1 ]
Matsuda, Akihiko [1 ]
Kanozawa, Koichi [1 ]
Araki, Nobuo [3 ]
Mitarai, Tetsuya [1 ]
机构
[1] Saitama Med Univ, Saitama Med Ctr, Dept Hypertens & Nephrol, Kawagoe, Saitama 3508550, Japan
[2] Kawagoe Ekimae Clin, Kawagoe, Saitama, Japan
[3] Saitama Med Univ, Fac Med, Dept Neurol, Moroyama, Saitama, Japan
[4] Saitama Med Univ, Fac Med, Dept Physiol, Moroyama, Saitama, Japan
来源
NEPHRON EXPERIMENTAL NEPHROLOGY | 2012年 / 122卷 / 3-4期
关键词
Pioglitazone; Diabetic nephropathy; Glomerular hyperfiltration; Macula densa; Tubuloglomerular feedback; TUBULOGLOMERULAR FEEDBACK; RENAL INJURY; SODIUM-REABSORPTION; PPAR-GAMMA; AFFERENT ARTERIOLE; NITRIC-OXIDE; EARLY-STAGE; IN-VIVO; MELLITUS; MICE;
D O I
10.1159/000348661
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background/Aims: Pioglitazone (PGZ), one of the thiazolidinediones, has been known to show renoprotective effects. In this study, we focused on the effect of PGZ on glomerular hyperfiltration (GHF), resultant glomerular injury and altered macula densa signaling as a cause of sustained GHF through modified tubuloglomerular feedback in rats with diabetic nephropathy. Methods: Kidneys from 24-week-old male OLETF rats and LET rats, nondiabetic controls, were used for the experiment. PGZ was administered (10 mg/kg/day, p.o.) for 2 weeks from 22 to 24 weeks of age in some of the OLETF rats (OLETF+ PGZ). Results: Parameters relating GHF, kidney weight, creatinine clearance, urine albumin/creatinine ratio and glomerular surface were all increased in OLETF rats and partially restored in OLETF+ PGZ rats. Expressions of desmin and TGF-beta were also increased in OLETF rats and restored in OLETF+PGZ rats. The changes in TGF-beta expression were confirmed to be independent of podocyte number. Finally, the immunoreactivity of neuronal nitric oxide synthase (nNOS) and cyclooxygenase 2 (COX-2) in the macula densa was assessed for the evaluation of macula densa signaling. Altered intensities of nNOS and COX-2 in OLETF rats were restored in OLETF+PGZ rats, which agreed with the gene expression analysis (nNOS: 100.2 +/- 2.9% in LET, 64.2 +/- 2.7% in OLETF, 87.4 +/- 12.1% in OLETF+PGZ; COX-2: 100.8 +/- 7.4% in LET, 249.2 +/- 19.4% in OLETF, 179.9 +/- 13.5% in OLETF+PGZ; n = 5) and the semiquantitative analysis of nNOS/COX-2-positive cells. Conclusion: PGZ effectively attenuated the GHF and hyperfiltration-associated glomerular injury in diabetic nephropathy. The restoration of altered macula densa signaling might be involved in the renoprotective effect of PGZ. Copyright (C) 2013 S. Karger AG, Basel
引用
收藏
页码:83 / 94
页数:12
相关论文
共 56 条
[31]   PPARγ agonists do not directly enhance basal or insulin-stimulated Na+ transport via the epithelial Na+ channel [J].
Nofziger, C ;
Chen, LH ;
Shane, MA ;
Smith, CD ;
Brown, KK ;
Blazer-Yost, BL .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2005, 451 (03) :445-453
[32]   Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation [J].
Ohga, Sakiko ;
Shikata, Kenichi ;
Yozai, Kosuke ;
Okada, Shinichi ;
Ogawa, Daisuke ;
Usui, Hitomi ;
Wada, Jun ;
Shikata, Yasushi ;
Makino, Hirofumi .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2007, 292 (04) :F1141-F1150
[33]   Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients [J].
Pistrosch, F ;
Herbrig, K ;
Kindel, B ;
Passauer, J ;
Fischer, S ;
Gross, P .
DIABETES, 2005, 54 (07) :2206-2211
[34]   TUBULAR SODIUM HANDLING AND TUBULOGLOMERULAR FEEDBACK IN EXPERIMENTAL DIABETES-MELLITUS [J].
POLLOCK, CA ;
LAWRENCE, JR ;
FIELD, MJ .
AMERICAN JOURNAL OF PHYSIOLOGY, 1991, 260 (06) :F946-F952
[35]   Glomerular hyperfiltration and increased proximal sodium reabsorption in subjects with type 2 diabetes or impaired fasting glucose in a population of the African region [J].
Pruijm, Menno ;
Wuerzner, Gregoire ;
Maillard, Marc ;
Bovet, Pascal ;
Renaud, Claude ;
Bochud, Murielle ;
Burnier, Michel .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2010, 25 (07) :2225-2231
[36]   Protection of the kidney by thiazolidinediones: An assessment from bench to bedside [J].
Sarafidis, P. A. ;
Bakris, G. L. .
KIDNEY INTERNATIONAL, 2006, 70 (07) :1223-1233
[37]   Glomerulotubular balance, dietary protein, and the renal response to glycine in diabetic rats [J].
Slomowitz, LA ;
Deng, AH ;
Hammes, JS ;
Gabbai, F ;
Thomson, SC .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2002, 282 (04) :R1096-R1103
[38]   Advective transport of nitric oxide in a mathematical model of the afferent arteriole [J].
Smith, KM ;
Moore, LC ;
Layton, HE .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2003, 284 (05) :F1080-F1096
[39]   Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal rats [J].
Song, J ;
Knepper, MA ;
Hu, XQ ;
Verbalis, JG ;
Ecelbarger, CA .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 308 (02) :426-433
[40]   The role of SGK-1 in angiotensin II-mediated sodium reabsorption in human proximal tubular cells [J].
Stevens, Veronica A. ;
Saad, Sonia ;
Poronnik, Philip ;
Fenton-Lee, Carol A. ;
Polhill, Tania S. ;
Pollock, Carol A. .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2008, 23 (06) :1834-1843