Physiology and Pathophysiology of Heme

Abstract

An iron-containing, tetrapyrrole ring, heme is an essential prosthetic group in an array of proteins that comprehensively affect cellular function and metabolism; yet "free" heme in sufficient amounts can be damaging to the kidney and other organs because of its bioreactivity and pro-oxidant effects. This review discusses the cellular metabolism of heme in health and disease and covers such areas as the synthesis of heme and its utilization in heme proteins; mechanisms underlying the toxicity of heme; and the extent to which pathophysiologic processes, such as renal incorporation of heme proteins or destabilization of intracellular heme proteins, increase intracellular levels of heme and provoke renal injury. The main catabolic process that degrades heme, the heme oxygenase (HO) system, is reviewed, and evidence for the protective effects of HO-1 against acute and chronic heme/heme protein-induced renal injury is summarized. Finally, current views regarding the molecular basis for heme-induced upregulation of HO-1 are discussed.

AKI Associated with Macroscopic Glomerular Hematuria

“…Hemoglobin is bound to haptoglobin, forming a haptoglobin-hemoglobin complex in plasma (38). Under normal conditions, this complex is too large to be filtered by glomeruli, and it is further degraded by spleen, bone marrow, and liver.…”

“…By contrast, free hemoglobin accumulates in plasma and dissociates from tetrameric to dimeric hemoglobin, which is filtered more easily by glomeruli. In the tubular lumen, hemoglobin may be taken up by proximal tubules (38) or may be degraded, releasing heme-containing molecules and free iron (9) (Figure 2).…”

Microsomal Prostaglandin E Synthase Type 2 (mPGES2) Is a Glutathione-dependent Heme Protein, and Dithiothreitol Dissociates the Bound Heme to Produce Active Prostaglandin E2 Synthase in Vitro

“…S4. The cellular levels of free heme have been reported to be submicromolar (13)(14)(15)(16)(17). With this heme dissociation constant, Ͼ97% of mPGES2 is predicted to be in the heme-bound form if the concentrations of free heme and mPGES2 in the cells are 100 and 1 nM, respectively.…”

Hematuria is a risk factor towards end-stage renal disease - A propensity score analysis

“…Hematuria could induce renal tubular epithelial cell damage by the cytotoxic, oxidant and inflammatory effects of hemoglobin-related molecules such as heme and iron [28]. Erythrocyte passage across the glomerular filtration barrier induces mechanical stress to erythrocyte, leading to leakage of hemoglobin from erythrocyte.…”

“…Free heme is extremely toxic, promoting lipid oxidation, inducing apoptosis and releasing inflammatory chemokines [30]. This heme-induced oxidation and inflammation in tubular cells could be related to CKD progression in the patients presenting microscopic hematuria [28]. Future studies are needed to elucidate the mechanism how hematuria exacerbates kidney damage in CKD milieu.…”