Renal C3 Complement Component: Feed Forward to Diabetic Kidney Disease

Abstract

Background: Diabetic nephropathy is the main cause of end-stage renal disease and has reached epidemic proportions. Methods: Comprehensive genomic profiling (RNAseq) was employed in the ZS (F₁ hybrids of Zucker and spontaneously hypertensive heart failure) model of diabetic nephropathy. Controls were lean littermates. Results: Diabetic nephropathy in obese, diabetic ZS was accelerated by a single episode of renal ischemia (DI). This rapid renal decline was accompanied by the activation of the renal complement system in DI, and to a lesser extent in sham-operated diabetic rats (DS). In DI there were significant increases in renal mRNA encoding C3, C4, C5, C6, C8, and C9 over sham-operated lean normal controls (LS). Moreover, mRNAs encoding the receptors for the anaphylatoxins C3a and C5a were also significantly increased in DI compared to LS. The classic complement pathway was activated in diabetic kidneys with significant increases of C1qa, C1qb, and C1qc mRNAs in DI over LS. In addition, critical regulators of complement activation were significantly attenuated in DI and DS. These included mRNAs encoding CD55, decay accelerating factor, and CD59, which inhibit the membrane attack complex. C3, C4, and C9 proteins were demonstrated in renal tubules and glomeruli. The complement RNAseq data were incorporated into a gene network showing interactions among C3-generating renal tubular cells and other immune competent migratory cells. Conclusions: We conclude that local activation of the complement system mediates renal injury in diabetic nephropathy.

Renal iron overload in rats with diabetic nephropathy

“…The inciting mechanisms of renal C3 activation were likely ischemic and prooxidant, as detailed in earlier work (Kelly et al. , ). It is also noteworthy that the source of the renal prooxidant state in ischemia is in part derived from renal iron, as shown in isolated kidneys (de Vries et al.…”

“…The original quantification and histology images have been shown in earlier publications (Kelly et al. , ). Here we show the distribution of renal ferric ferrocyanide, or tissue iron, in LS, DS, and DI at 28 weeks of age, and also in DI at 36 weeks of age (Fig.…”

“…On the right side of Fe it is shown that renal C3 component activation (Kelly et al. ) and Alox (Arachidonate lipoxygenase) are activated by iron loads. C3 activation leads to cell death via its derived C3b component (Kelly et al.…”

“…C3 activation leads to cell death via its derived C3b component (Kelly et al. ), and Alox is involved in lipid peroxidation. Iron itself induces oxidant stress and renal fibrosis via upregulated TGF beta.…”

“…This approach showed that obese, diabetic ZS rats with renal ischemia exhibited general activation of the renal complement system along with interacting proinflammatory gene networks (Kelly et al. ). The inciting mechanisms of renal C3 activation were likely ischemic and prooxidant, as detailed in earlier work (Kelly et al.…”