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Sex-differences in renal expression of selected transporters and transcription factors in lean and obese Zucker spontaneously hypertensive fatty rats.

Babelova A, Burckhardt BC, Wegner W, Burckhardt G, Henjakovic M - J Diabetes Res (2015)

Bottom Line: Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1β and Hnf4α in both sexes.Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors.However, OAT2-dependent uptake of cGMP was inhibited by furosemide.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cardiovascular Physiology (Physiology I), Faculty of Medicine, Goethe-University, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany ; Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 83391 Bratislava, Slovakia.

ABSTRACT
The aim of this study was to identify sex-dependent expression of renal transporter mRNA in lean and obese Zucker spontaneously hypertensive fatty (ZSF1) rats and to investigate the interaction of the most altered transporter, organic anion transporter 2 (Oat2), with diabetes-relevant metabolites and drugs. Higher incidence of glomerulosclerosis, tubulointerstitial fibrosis, and protein casts in Bowman's space and tubular lumen was detected by PAS staining in obese male compared to female ZSF1 rats. Real-time PCR on RNA isolated from kidney cortex revealed that Sglt1-2, Oat1-3, and Oct1 were higher expressed in kidneys of lean females. Oct2 and Mrp2 were higher expressed in obese males. Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1β and Hnf4α in both sexes. The highest difference between lean and obese ZSF1 rats was found for Oat2. Therefore, we have tested the interaction of human OAT2 with various substances using tritium-labeled cGMP. Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors. However, OAT2-dependent uptake of cGMP was inhibited by furosemide. The strongly decreased expression of Oat2 and other transporters in female diabetic ZSF1 rats could possibly impair renal drug excretion, for example, of furosemide.

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Related in: MedlinePlus

PAS staining in renal cortical slices. Renal sections of lean (le) and obese (ob) ZSF1 rats were stained with PAS and structural changes were analyzed. Examples for histological changes in renal tissue are marked as follows: #, tubular atrophy and dilatation; ##, hyaline protein casts in tubular lumen; §, pressure-induced deformation of glomerulus; §§, dilatation of Bowman's capsule and protein cast in Bowman's space; §§§, glomerulosclerosis. The arrows mark the thickening of tubular and glomerular basement membranes. Magnification: 200x. Representative images from three different rats under each condition are shown.
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fig1: PAS staining in renal cortical slices. Renal sections of lean (le) and obese (ob) ZSF1 rats were stained with PAS and structural changes were analyzed. Examples for histological changes in renal tissue are marked as follows: #, tubular atrophy and dilatation; ##, hyaline protein casts in tubular lumen; §, pressure-induced deformation of glomerulus; §§, dilatation of Bowman's capsule and protein cast in Bowman's space; §§§, glomerulosclerosis. The arrows mark the thickening of tubular and glomerular basement membranes. Magnification: 200x. Representative images from three different rats under each condition are shown.

Mentions: Light microscopy of periodic acid-Schiff stained sections revealed differences between lean females and lean males in the structure of glomeruli and tubuli of ZSF1 rats (Figure 1, le-female, le-male). Whereas the structure of glomeruli was similar between the two sexes, the tubular basement membrane of lean males appeared to be thicker than that of lean females (arrows). Sex-differences became more obvious in obese rats where renal damage was more prominent in obese males than in obese female ZSF1 rats. In kidneys of obese male and female ZSF1 rats, glomerulosclerosis, extensive mesangial matrix accumulation, and mesangial hypercellularity were detected (Figure 1, §§§). In obese males, in addition, a dilatation of Bowman's capsule and tuft-to-capsule adhesion was present (§§). Tubular injury was indicated by the thickening of tubular basement membrane, tubular dilatation with epithelial cell flattening, tubular lesions, and lumen containing protein as well as by atrophic tubuli (#) with hyaline casts (Figure 1, ##).


Sex-differences in renal expression of selected transporters and transcription factors in lean and obese Zucker spontaneously hypertensive fatty rats.

Babelova A, Burckhardt BC, Wegner W, Burckhardt G, Henjakovic M - J Diabetes Res (2015)

PAS staining in renal cortical slices. Renal sections of lean (le) and obese (ob) ZSF1 rats were stained with PAS and structural changes were analyzed. Examples for histological changes in renal tissue are marked as follows: #, tubular atrophy and dilatation; ##, hyaline protein casts in tubular lumen; §, pressure-induced deformation of glomerulus; §§, dilatation of Bowman's capsule and protein cast in Bowman's space; §§§, glomerulosclerosis. The arrows mark the thickening of tubular and glomerular basement membranes. Magnification: 200x. Representative images from three different rats under each condition are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4325971&req=5

fig1: PAS staining in renal cortical slices. Renal sections of lean (le) and obese (ob) ZSF1 rats were stained with PAS and structural changes were analyzed. Examples for histological changes in renal tissue are marked as follows: #, tubular atrophy and dilatation; ##, hyaline protein casts in tubular lumen; §, pressure-induced deformation of glomerulus; §§, dilatation of Bowman's capsule and protein cast in Bowman's space; §§§, glomerulosclerosis. The arrows mark the thickening of tubular and glomerular basement membranes. Magnification: 200x. Representative images from three different rats under each condition are shown.
Mentions: Light microscopy of periodic acid-Schiff stained sections revealed differences between lean females and lean males in the structure of glomeruli and tubuli of ZSF1 rats (Figure 1, le-female, le-male). Whereas the structure of glomeruli was similar between the two sexes, the tubular basement membrane of lean males appeared to be thicker than that of lean females (arrows). Sex-differences became more obvious in obese rats where renal damage was more prominent in obese males than in obese female ZSF1 rats. In kidneys of obese male and female ZSF1 rats, glomerulosclerosis, extensive mesangial matrix accumulation, and mesangial hypercellularity were detected (Figure 1, §§§). In obese males, in addition, a dilatation of Bowman's capsule and tuft-to-capsule adhesion was present (§§). Tubular injury was indicated by the thickening of tubular basement membrane, tubular dilatation with epithelial cell flattening, tubular lesions, and lumen containing protein as well as by atrophic tubuli (#) with hyaline casts (Figure 1, ##).

Bottom Line: Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1β and Hnf4α in both sexes.Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors.However, OAT2-dependent uptake of cGMP was inhibited by furosemide.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cardiovascular Physiology (Physiology I), Faculty of Medicine, Goethe-University, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany ; Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 83391 Bratislava, Slovakia.

ABSTRACT
The aim of this study was to identify sex-dependent expression of renal transporter mRNA in lean and obese Zucker spontaneously hypertensive fatty (ZSF1) rats and to investigate the interaction of the most altered transporter, organic anion transporter 2 (Oat2), with diabetes-relevant metabolites and drugs. Higher incidence of glomerulosclerosis, tubulointerstitial fibrosis, and protein casts in Bowman's space and tubular lumen was detected by PAS staining in obese male compared to female ZSF1 rats. Real-time PCR on RNA isolated from kidney cortex revealed that Sglt1-2, Oat1-3, and Oct1 were higher expressed in kidneys of lean females. Oct2 and Mrp2 were higher expressed in obese males. Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1β and Hnf4α in both sexes. The highest difference between lean and obese ZSF1 rats was found for Oat2. Therefore, we have tested the interaction of human OAT2 with various substances using tritium-labeled cGMP. Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors. However, OAT2-dependent uptake of cGMP was inhibited by furosemide. The strongly decreased expression of Oat2 and other transporters in female diabetic ZSF1 rats could possibly impair renal drug excretion, for example, of furosemide.

Show MeSH
Related in: MedlinePlus