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Am J Physiol Renal Physiol 296: F598-F604, 2009. First published December 23, 2008; doi:10.1152/ajprenal.00074.2008
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Abnormal autoregulation and tubuloglomerular feedback in prediabetic and diabetic OLETF rats

Seiji Hashimoto,1 Kanji Yamada,1 Tetsuya Kawata,1 Toshio Mochizuki,1 Jurgen Schnermann,2 and Takao Koike1

1Hokkaido University Graduate School of Medicine, Internal Medicine II, Sapporo, Japan; and 2National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland

Submitted 24 August 2008 ; accepted in final form 16 December 2008

The mechanisms underlying the development and prevention of diabetic nephropathy are still not fully understood. In the present study in the Otsuka Long-Evans Tokushima Fatty (OLETF) model of type 2 diabetic rats, we investigated whether renal hemodynamic abnormalities exist and whether they precede the onset of diabetes. Using OLETF rats in both prediabetic and diabetic stages, we assessed autoregulatory responses of total renal blood flow (RBF) and of superficial (SBF) and deep renal cortical (DBF) blood flow to stepwise reductions of renal perfusion pressure (RPP) induced by a manual clamp on the abdominal aorta. During clamp-induced reductions of RPP by 10 or 20 mmHg, RBF fell significantly more in OLETF rats than in lean control [Long-Evans Tokushima Otsuka (LETO)] rats. Whereas SBF showed no significant changes in either OLETF rats or LETO rats during mild clamping, DBF decreased significantly more in OLETF rats than LETO rats. Reduced autoregulatory efficiency in OLETF rats was observed in both prediabetic and diabetic stages. Micropuncture studies showed that tubuloglomerular feedback (TGF) responses of stop flow pressure are reduced in prediabetic (–7.3 vs. –25.7%) as well as in diabetic OLETF rats compared with LETO control rats (–4.4 vs. –18.8%). Renal corticotomy was performed to measure glomerular capillary pressure (Pgc) directly. Pgc of deep cortical glomeruli was higher than superficial glomerular Pgc in both strains of rats, but the difference was especially pronounced in OLETF rats (deep 78 ± 2 vs. superficial 57 ± 4 mmHg). This study demonstrates reduced autoregulatory adjustments and impaired TGF efficiency in prediabetic OLETF rats. Thus abnormal RBF regulation precedes the onset of diabetes and is especially pronounced in the deep cortical region.

type 2 diabetes; hemodynamics; deep nephrons; corticotomy; micropuncture; Otsuka Long-Evans Tokushima Fatty


Address for reprint requests and other correspondence: S. Hashimoto, Hokkaido Univ. Graduate School of Medicine, Internal Medicine II, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan (e-mail: seijinih{at}med.hokudai.ac.jp)






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