The Heme Oxygenase System Suppresses Perirenal Visceral Adiposity, Abates Renal Inflammation and Ameliorates Diabetic Nephropathy in Zucker Diabetic Fatty Rats

Abstract

The growing incidence of chronic kidney disease remains a global health problem. Obesity is a major risk factor for type-2 diabetes and renal impairment. Perirenal adiposity, by virtue of its anatomical proximity to the kidneys may cause kidney disease through paracrine mechanisms that include increased production of inflammatory cytokines. Although heme-oxygenase (HO) is cytoprotective, its effects on perirenal adiposity and diabetic nephropathy in Zucker-diabetic fatty rats (ZDFs) remains largely unclear. Upregulating the HO-system with hemin normalised glycemia, reduced perirenal adiposity and suppressed several pro-inflammatory/oxidative mediators in perirenal fat including macrophage-inflammatory-protein-1α (MIP-1α), endothelin (ET-1), 8-isoprostane, TNF-α, IL-6 and IL-1β. Furthermore, hemin reduced ED1, a marker of pro-inflammatory macrophage-M1-phenotype, but interestingly, enhanced markers associated with anti-inflammatory M2-phenotype such as ED2, CD206 and IL-10, suggesting that hemin selectively modulates macrophage polarization towards the anti-inflammatory M2-phenotype. These effects were accompanied by increased adiponectin, HO-1, HO-activity, atrial-natriuretic peptide (ANP), and its surrogate marker, urinary-cGMP. Furthermore, hemin reduced renal histological lesions and abated pro-fibrotic/extracellular-matrix proteins like collagen and fibronectin that deplete nephrin, an important transmembrane protein which forms the scaffolding of the podocyte slit-diaphragm allowing ions to filter but not massive excretion of proteins, hence proteinuria. Correspondingly, hemin increased nephrin expression in ZDFs, reduced markers of renal damage including, albuminuria/proteinuria, but increased creatinine-clearance, suggesting improved renal function. Conversely, the HO-blocker, stannous-mesoporphyrin nullified the hemin effects, aggravating glucose metabolism, and exacerbating renal injury and function. The hemin effects were less-pronounced in Zucker-lean controls with healthy status, suggesting greater selectivity of HO in ZDFs with disease. We conclude that the concomitant reduction of pro-inflammatory/oxidative mediators, macrophage infiltration and profibrotic/extracellular-matrix proteins, coupled to increased nephrin, adiponectin, ANP, cGMP and creatinine clearance may account for improved renal function in hemin-treated ZDFs. These findings suggest that HO-inducers like hemin may be explored against the co-morbidity of perirenal adiposity and diabetic nephropathy.

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

“…Increasing evidence shows that MIP-1 α is overproduced and functionally activated to induce migration of T cells and macrophages to the kidney during diabetic and nondiabetic chronic kidney diseases [273, 274]. MIP-1 α is increased in urine of patients with crescentic glomerulonephritis, whereas its cognate receptors, CCR1 and CCR5, are expressed In CD3 ++ T cells and CD 68 + macrophages which infiltrate the glomeruli and interstitium.…”

Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome

“…Induction of HO-1 by several inducers such L-4F, CoPP, heme, or by gene transfer 4,113,114,172,174–176 is associated with an increased number of healthy adipocytes, a concomitant increase of plasma adiponectin levels, improved insulin sensitivity and a decrease in inflammatory adipokines and blood pressure 20,24,115,172,174,175,177 . This effect of HO-1 induction on adipocyte morphology was confirmed in Zucker diabetic rats 175 and extended to ob/ob diabetic mice, where increased levels of HO-1 and HO activity prevented weight gain and decreased visceral and subcutaneous fat levels. Additional studies have reported that upregulation of HO-1 decreases adipogenesis in mesenchymal stem cells (MSCs) and increases adiponectin levels in culture media, which is reversed by the inhibition of HO activity 4,114 .…”

Targeting heme oxygenase-1 in early diabetic nephropathy in streptozotocin-induced diabetic rats

“…1), which would greatly improve glucose metabolism, through enhanced adenosine monophosphate-activated protein kinasedependent glucose transporter 4 (GLUT4) expression and translocation (15). The antidiabetic effect observed with CoPP could be due to potentiation of insulin-sensitizing pathways (22) through HO upregulation similarly to increases in the activity of other factors which also promote insulin signaling such as adiponectin (22,(37)(38)(39)(40), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (36), and peroxisome proliferatoractivated receptor α (36).…”

“…The pathophysiological activation of HO-1 may fall below the threshold necessary to activate important components through which the HO system can restore tissue homeostasis. Stronger effects can be achieved by some pharmacological agents capable of inducing some HO, like metalloprotoporphyrins such as cobalt protoporphyrin (CoPP) (39).…”