Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/ disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/ RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/ disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones.

Small nuclear RNA and associated lupus autoantigens activate B cells and dendritic cells via Toll-like receptor-7 (TLR-7); therefore, TLR-7 may represent a potential therapeutic target in lupus. MRL lpr mice were administered an injection of either saline or synthetic oligodeoxynucleotides with immunoregulatory sequences (IRS) that specifically block signaling via TLR-7 (IRS 661) or via TLR-7 and TLR-9 (IRS 954, which uses a active sequence from IRS 661 along with a TLR-9 inhibitory sequence) from weeks 11 to 24 of age. IRS 661 and IRS 954 both significantly reduced the weight of spleen and lymph nodes as well as serum levels of TNF as compared with saline-treated MRL lpr mice. Only IRS 661 but not IRS 954 significantly reduced serum levels of IL-12p40, anti-dsDNA IgG 2a , IgG 2b , and anti-Smith IgG. Both IRS localized to the kidney after intraperitoneal injection and significantly improved the activity index and chronicity index for lupus nephritis in MRL lpr mice. This was associated with significant reduction of renal glomerular and interstitial macrophage infiltrates and the number of interstitial T cells. Autoimmune lung injury was also attenuated with IRS 661 and IRS 954. These data demonstrate that TLR-7 antagonism, initiated after the onset of autoimmunity, can prevent autoimmune kidney and lung injury in MRL lpr mice. Concomitant blockade of TLR-9 with IRS 954 neutralized the effect of TLR-7 blockade on dsDNA IgG 2a , dsDNA IgG 2b , and Smith antigen autoantibodies but had neither additive nor opposing effects on autoimmune lung and kidney injury. Hence, TLR-7 is proposed as a novel and potential therapeutic target in systemic lupus erythematosus.

The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the L-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic D-RNA. Autoimmune-prone MRL lpr/lpr mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36 -based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.