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

Asakura, Juko; Hasegawa, Hajime; Takayanagi, Kaori; Shimazu, Tomokazu; Suge, Rie; Shimizu, Taisuke; Iwashita, Takatsugu; Tayama, Yosuke; Matsuda, Akihiko; Kanozawa, Koichi; Araki, Nobuhito; Mitarai, Tetsuya

doi:10.1159/000348661

Cited by 14 publications

(13 citation statements)

References 100 publications

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“…Serum creatinine and blood urea nitrogen (BUN) levels were not increased in OLETF at this age compared with the levels in LETO (Table 1). However, consistent with previous reports 27, 28 , OLETF showed higher urine albumin/creatinine and urine protein/creatinine ratios and greater kidney weight than those in LETO (Table 1). In addition, periodic acid-Schiff (PAS) staining showed that the mesangial areas tended to be increased and that the glomerular areas were significantly enlarged in OLETF compared with those in LETO (Supplementary Fig.…”

Section: Resultssupporting

confidence: 93%

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

Muratsubaki

Kuno

Tanno

et al. 2017

Sci Rep

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Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we hypothesized that suppression of autophagic response underlies aggravation of renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal artery in the contralateral kidney. Levels of serum creatinine and blood urea nitrogen and tubular injury score after I/R were significantly higher in OLETF than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic activation in response to I/R and significantly attenuated I/R-induced renal injury. Collectively, these findings indicate that suppressed autophagic activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.

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Section: Resultssupporting

confidence: 93%

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

Muratsubaki

Kuno

Tanno

et al. 2017

Sci Rep

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“…After urine collection for 24 h, blood samples were obtained from the aorta, and the rats' kidneys were perfused with ice-cold PBS (pH 7.4) and quickly removed under anesthesia (50 mg/kg ip pentobarbital) at 16, 24, and 34 wks of age (n ϭ 6). For the biochemical analysis of blood and urine samples, except Mg 2ϩ , all were measured according to published methods (3,57). Serum and urine Mg 2ϩ concentrations were measured by colorimetric tests using xylidine blue.…”

Section: Methodsmentioning

confidence: 99%

“…Sections (4 m) were prepared and stained with periodic acid-Schiff and Masson trichrome. Immunohistochemical stainings were performed as previously described (3). The other paraffin sections were treated with primary antibody, rabbit anti-TRPM6 (Osenses, Keswick, SA, Australia), diluted 1:15,000, rabbit anti-Na ϩ -Cl Ϫ cotransporter (NCC; Merck, Darmstadt, Germany), diluted 1:8,000, mouse anti-␣-smooth muscle actin (␣-SMA; Progen Biotechnik, Heidelberg, Germany), diluted 1:2,500 for 16 h at 4°C, or mouse anti-Na ϩ -Ca 2ϩ exchanger 1 (NCX1; Swant Swiss Antibodies, Marly, Switzerland) diluted 1:2,000 for 1 h at room temperature followed by Dako Cytomation EnVision plus System HRP-Labeled Polymer (Dako, Glostrup, Denmark) or Histofine Simple Stain Rat MAX PO (M) (Nichirei Biosciences, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

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Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats

Takayanagi

Shimizu

Tayama

et al. 2015

American Journal of Physiology-Renal Physiology

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We assessed the expression profile of Mg(2+)-transporting molecules in obese diabetic rats as a cause of hypermagnesiuric hypomagnesemia, which is involved in the development of insulin resistance, hypertension, and coronary diseases. Kidneys were obtained from male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) obese diabetic rats at the ages of 16, 24, and 34 wk. Expression profiles were studied by real-time PCR and immunohistochemistry together with measurements of urine Mg(2+) excretion. Urine Mg(2+) excretion was increased in 24-wk-old OLETF rats and hypomagnesemia was apparent in 34-wk-old OLETF rats but not in LETO rats (urine Mg(2+) excretion: 0.16 ± 0.01 μg·min(-1)·g body wt(-1) in 24-wk-old LETO rats and 0.28 ± 0.01 μg·min(-1)·g body wt(-1) in 24-wk-old OLETF rats). Gene expression of transient receptor potential (TRP)M6 was downregulated (85.5 ± 5.6% in 34-wk-old LETO rats and 63.0 ± 3.5% in 34-wk-old OLETF rats) concomitant with Na(+)-Cl(-) cotransporter downregulation, whereas the expression of claudin-16 in tight junctions of the thick ascending limb of Henle was not different. The results of the semiquantitative analysis of immunohistochemistry were consistent with these findings (TRPM6: 0.49 ± 0.04% in 16-wk-old LETO rats, 0.10 ± 0.01% in 16-wk-old OLETF rats, 0.52 ± 0.03% in 24-wk-old LETO rats, 0.10 ± 0.01% in 24-wk-old OLETF rats, 0.48 ± 0.02% in 34-wk-old LETO rats, and 0.12 ± 0.02% in 34-wk-old OLETF rats). Gene expression of fibrosis-related proinflammatory cytokines as well as histological changes showed that the hypermagnesiuria-related molecular changes and tubulointerstitial nephropathy developed independently. TRPM6, located principally in distal convoluted tubules, appears to be a susceptible molecule that causes hypermagnesiuric hypomagnesemia as a tubulointerstitial nephropathy-independent altered tubular function in diabetic nephropathy.

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“…The biochemical measurements of blood urea nitrogen, creatinine, sodium, and potassium were all performed as described [21]. The rats' serum and urine magnesium concentrations were measured by a colorimetric test using xylidine blue.…”

Section: Serum Biochemistrymentioning

confidence: 99%

Down-regulation of magnesium transporting molecule, claudin-16, as a possible cause of hypermagnesiuria with the development of tubulo-interstitial nephropathy

et al. 2018

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Background/Aims. Tubulo-interstitial nephropathy (TIN) is a critical pathological setting for the renal prognosis, and an increase in the urine magnesium excretion is a well-known characteristic feature as one of clinical parametets for the assessment of TIN. We examined the correlation between the development of TIN and the changes in the mRNA expression of renal magnesium-transporting molecules in rats with unilateral ureter obstruction (UUO). Methods. Ureter-ligated kidney was sampled at day-0 (control), day-1 (early phase) and day-7 (late phase). The development of TIN was assessed by immunohistochemistry and the real-time PCR of fibrosis-related genes (MCP-1: 105.1 ± 14.8% on day-0, 132.9 ± 25.7% on day-1, 302.7 ± 32.7% on day-7, TGF-␤: 101.1 ± 7.6% on day-0, 93.6 ± 4.1% on day-1, 338.9 ± 20.7% on day-7) . The respective expressions of claudin-10, 14, 16, 19, and transient receptor potential (TRP) M6 as magnesium-transporting molecules were also studied. The expression of calcium sensing receptor (CaSR) as an inhibitory regulator of claudin-14 was additionally studied. Results. The gene expression of claudin-16 was decreased in the late phase of UUO (100.2 ± 2.9% at day-0, 90.3 ± 6.3% at day-1, 36.4 ± 1.6% at day-7) which was consistent with the increased urine magnesium excretion. Immunohistochemistry showed an apparent reduction of the immunoreactivity of claudin-16 in the late phase. The expression of TRPM6 was reduced even in the early phase. The immunohistochemistry and gene expression of MCP-1 and TGF-ß showed that TIN was not apparent in the early phase but was significant in the late phase of UUO. The density of peritubular capillaries was diminished in the late phase but not in the early phase. Expression of claudin-14 and CaSR was up-and down-regulated, respectively. Conclusion. Our findings may indicate that the characteristic hypermagnesiuria in TIN is principally caused by the dysfunction of magnesium reabsorption in the thick ascending limb of Henle resulting from a significant decrease in the claudin-16 expression. The down-regulation might be closely related to the development of TIN.

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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

Cited by 14 publications

References 100 publications

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats

Down-regulation of magnesium transporting molecule, claudin-16, as a possible cause of hypermagnesiuria with the development of tubulo-interstitial nephropathy

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