Hemin Therapy Improves Kidney Function in Male Streptozotocin-Induced Diabetic Rats: Role of the Heme Oxygenase/Atrial Natriuretic Peptide/Adiponectin Axis

Abstract

Diabetic nephropathy is characterized by elevated macrophage infiltration and inflammation. Although heme-oxygenase (HO) is cytoprotective, its role in macrophage infiltration and nephropathy in type 1 diabetes is not completely elucidated. Administering the HO inducer, hemin, to streptozotocin-diabetic rats suppressed renal proinflammatory macrophage-M1 phenotype alongside several proinflammatory agents, chemokines, and cytokines including macrophage inflammatory protein 1α (MIP-1α), macrophage-chemoattractant protein-1 (MCP-1), TNF-α, IL-1β, IL-6, nuclear factor-κB (NF-κB), and aldosterone, a stimulator of the inflammatory/oxidative transcription factor, NF-κB. Similarly, hemin therapy attenuated extracellular matrix/profibrotic proteins implicated in renal injury including fibronectin, collagen-IV, and TGF-β1 and reduced several renal histopathological lesions such as glomerulosclerosis, tubular necrosis, tubular vacuolization, and interstitial macrophage infiltration. Furthermore, hemin reduced markers of kidney dysfunction like proteinuria and albuminuria but increased creatinine clearance, suggesting improved kidney function. Correspondingly, hemin significantly enhanced the antiinflammatory macrophage-M2 phenotype, IL-10, adiponectin, HO-1, HO activity, and atrial natriuretic-peptide (ANP), a substance that abates TNF-α, IL-6, and IL-1β, with parallel increase of urinary cGMP, a surrogate marker of ANP. Contrarily, coadministering the HO inhibitor, chromium-mesoporphyrin with the HO-inducer, hemin nullified the antidiabetic and renoprotective effects, whereas administering chromium-mesoporphyrin alone abrogated basal HO activity, reduced basal adiponectin and ANP levels, aggravated hyperglycemia, and further increased MCP-1, MIP-1α, aldosterone, NF-κB, TNF-α, IL-6, IL-1β, proteinuria/albuminuria, and aggravated creatinine clearance, thus exacerbating renal dysfunction, suggesting the importance of the basal HO-adiponectin-ANP axis in renoprotection and kidney function. Collectively, these data suggest that hemin ameliorates diabetic nephropathy by selectively enhancing the antiinflammatory macrophage-M2 phenotype and IL-10 while concomitantly abating the proinflammatory macrophage-M1 phenotype and suppressing extracellular matrix/profibrotic factors with reduction of renal lesions including interstitial macrophage infiltration. Because aldosterone stimulate NF-κB, which activates cytokines like TNF-α, IL-6, IL-1β that in turn stimulate chemokines such as MCP-1 and MIP-1α to promote macrophage-M1 infiltration, the hemin-dependent potentiation of the HO-adiponectin-ANP axis may account for reduced macrophage infiltration and inflammatory insults in streptozotocin-diabetic rats.