Abstract
Hyperglycemia in diabetes alters tight junction (TJ) proteins in the kidney. We evaluated the participation of aldosterone (ALD), and the effect of spironolactone (SPL), a mineralocorticoid receptor antagonist, on the expressions of claudin-2, -4, -5 and -8, and occludin in glomeruli, proximal and distal tubules isolated from diabetic rats. Type 1 diabetes was induced in female Wistar rats by a single tail vein injection of streptozotocin (STZ), and SPL was administrated daily by gavage, from days 3–21. Twenty-one days after STZ injection the rats were sacrificed. In diabetic rats, the serum ALD levels were increased, and SPL-treatment did not have effect on these levels or in hyperglycemia, however, proteinuria decreased in SPL-treated diabetic rats. Glomerular damage, evaluated by nephrin and Wilm’s tumor 1 (WT1) protein expressions, and proximal tubular damage, evaluated by kidney injury molecule 1 (Kim-1) and heat shock protein 72 kDa (Hsp72) expressions, were ameliorated by SPL. Also, SPL prevented decrement in claudin-5 in glomeruli, and claudin-2 and occludin in proximal tubules by decreasing oxidative stress, evaluated by superoxide anion (O2●―) production, and oxidative stress markers. In distal tubules, SPL ameliorated increase in mRNA, protein expression, and phosphorylation in threonine residues of claudin-4 and -8, through a serum and glucocorticoid-induced kinase 1 (SGK1), and with-no-lysine kinase 4 (WNK4) signaling pathway. In conclusion, this is the first study that demonstrates that ALD modulates the expression of renal TJ proteins in diabetes, and that the blockade of its actions with SPL, may be a promising therapeutic strategy to prevent alterations of TJ proteins in diabetic nephropathy.
Highlights
The kidney plays a vital role in electrolyte homeostasis by mediating transepithelial reabsorption of water and ions, thereby determining the final composition of urine
We previously studied the impact of diabetes on renal cldns expressions, and described that diabetes decreases the expression of cldn-5 in glomeruli (GL), and cldn-2 and occldn in proximal tubules (PT), in an oxidative stress-dependent way
Based on the evidence above described, we studied the SPL effect to inhibit ALD actions in renal epithelia of diabetic rats, and to explore the mechanism through which ALD may modulate the expression of tight junction (TJ) proteins in GL, PT and distal tubules (DT) in early diabetic nephropathy
Summary
The kidney plays a vital role in electrolyte homeostasis by mediating transepithelial reabsorption of water and ions, thereby determining the final composition of urine. Specific sets of cldns are expressed along of different nephron segments (glomeruli and tubules), determining unique segmental paracelular permeability. Glomeruli express cldns, such as claudin-1, in parietal epithelial cells [4,5], and claudin-5 and -6 in capillaries [6,7,8]. Pore cldns, such as claudin-2, are associated with leakier segments, such as the proximal tubule, whereas barrier cldns, such as claudin-4 and -8, are expressed in the aldosterone-sensitive distal nephron (ASDN) [10]. Cldn-2 is considered a paracellular pore, which participates in water, and sodium reabsorption, in the proximal tubule [11]. Occludin (occldn) is another integral protein of the TJ, which has been located at the proximal tubule, but is more abundant in the distal segments from nephron [17]
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