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 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.

Advances in understanding the role of adiponectin in renal fibrosis

“…They found that APN decreased the expression of PAI‐1, FN and α‐SMA in the renal cortex following induction by DOCA‐salt combined with angiotensin II (Ang II). APN also decreased the expression of proinflammatory factors (NF‐κB‐p65 and pERK1/2) and oxidative stress‐related factors (NOX2 and p47phox), ameliorated renal fibrosis, reduced podocyte damage and reduced overall inflammation and oxidative stress 20 . APN inhibits the production of the pro‐inflammatory factor IL‐8 in a dose‐dependent manner.…”

“…They found that APN activated AMPK signalling pathways and thereby reduced Ang II‐mediated induction of PAI‐1, fibronectin (FN), α‐SMA and fibrosis indexes. APN therefore reduces the extent of renal fibrosis and damage of podocytes, and provides a renoprotective effect 20 …”

Combined donor-recipient genotypes of leptin receptor and adiponectin gene polymorphisms affect the incidence of complications after renal transplantation

“…Interestingly, these anti-inflammatory actions also take place locally in the kidney, as adiponectin receptors are present in renal cells [ 29 ]. Moreover, Tian et al recently showed in rodents that adiponectin is a renoprotective agent that attenuates kidney injury and fibrosis [ 30 ]. Therefore, our results, pointing to a beneficial effect of the SNP (as it was associated with better graft function), would be in line with those reports linking the T-variant allele with increased adiponectin activity [ 26 ].…”

Adiponectin in renal fibrosis

“…Moreover, many in vivo experiments have confirmed the anti-fibrotic action of APN in the kidney. The mRNA expression and deoxycorticosterone acetate-salt 30 and Ang II infusion-induced production of these fibrotic markers in the renal cortex were reduced in wild type mice showing APN overexpression [25].…”

“…Clinically, conditions such as diabetic nephropathy, immunoglobulin A nephropathy (IgAN), and lupus nephritis (LN), which are associated with CKD can precipitate renal fibrosis [21,22]. In recent years, a large number of studies have investigated the role of APN in renal fibrosis associated with these diseases, and the consensus based on the available literature confirms the renoprotective effect of APN [23][24][25]. Clinical and basic research has characterized the significant physiological role of APN, and a strong association has been observed between serum APN levels and outcomes of various renal diseases [26].…”