Adiponectin attenuates kidney injury and fibrosis in deoxycorticosterone acetate-salt and angiotensin II-induced CKD mice.

Abstract

Adiponectin (ApN) is a multifunctional adipokine. However, high, rather than low, concentrations of ApN are unexpectedly found in patients with chronic kidney disease (CKD) via an as yet unknown mechanism, and the role of ApN in CKD is unclear. Herein, we investigated the effect of ApN overexpression on progressive renal injury resulting from deoxycorticosterone acetate-salt (DOCA) and angiotensin II (ANG II) infusion using a transgenic, inducible ApN-overexpressing mouse model. Three groups of mice [wild type receiving no infusion (WT) and WT and cytochrome P450 1a1 (cyp1a1)-ApN transgenic mice (ApN-Tg) receiving DOCA+ANG II infusion (WT/DOCA+ANG II and ApN-Tg/DOCA+ANG II)] were assigned to receive normal food containing 0.15% of the transgene inducer indole-3-carbinol (I3C) for 3 wk. In the I3C-induced ApN-Tg/DOCA+ANG II mice, not the WT or WT/DOCA+ANG II mice, overexpression of ApN in liver resulted in 3.15-fold increases in circulating ApN compared with nontransgenic controls. Of note, the transgenic mice receiving DOCA+ANG II infusion were still hypertensive but had much less albuminuria and glomerular and tubulointerstitial fibrosis, which were associated with ameliorated podocyte injury determined by ameliorated podocyte loss and foot process effacement, and alleviated tubular injury determined by ameliorated mRNA overexpression of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and mRNA decreases of cubilin and megalin in tubular cells, compared with WT/DOCA+ANG II mice. In addition, renal production of NF-κB-p65, NAPDH oxidase 2, and p47 phox and MAPK-related cellular proliferation, which were induced in WT/DOCA+ANG II mice, were markedly reduced in ApN-Tg/DOCA+ANG II mice. These results indicate that elevated ApN in the CKD mouse model is renal protective. Enhancing ApN production or signaling may have therapeutic potential for CKD.

• Authors: Mi Tian, Li Tang, Yuanyuan Wu, Srinivasan Beddhu, Yufeng Huang
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 315 Issue 3 Pg. F558-F571 (09 01 2018) ISSN: 1522-1466 [Electronic] United States
• PMID: 29873514 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ADIPOQ protein, human
• Adiponectin
• Havcr1 protein, mouse
• Hepatitis A Virus Cellular Receptor 1
• Lipocalin-2
• Low Density Lipoprotein Receptor-Related Protein-2
• Lrp2 protein, mouse
• Receptors, Cell Surface
• Rela protein, mouse
• Transcription Factor RelA
• intrinsic factor-cobalamin receptor
• Angiotensin II
• Lcn2 protein, mouse
• Desoxycorticosterone Acetate
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases
• neutrophil cytosolic factor 1

Topics

• Adiponectin (genetics, metabolism)
• Angiotensin II
• Animals
• Cell Proliferation
• Desoxycorticosterone Acetate
• Disease Models, Animal
• Fibrosis
• Hepatitis A Virus Cellular Receptor 1 (genetics, metabolism)
• Kidney (metabolism, pathology)
• Lipocalin-2 (genetics, metabolism)
• Low Density Lipoprotein Receptor-Related Protein-2 (genetics, metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• NADPH Oxidase 2 (genetics, metabolism)
• NADPH Oxidases (genetics, metabolism)
• Nephrectomy
• Receptors, Cell Surface (genetics, metabolism)
• Renal Insufficiency, Chronic (chemically induced, genetics, metabolism, prevention & control)
• Signal Transduction
• Transcription Factor RelA (metabolism)
• Up-Regulation