Kallikreins and lupus nephritis

Abstract

The kidney kallikrein-kinin system plays important roles in inflammation, coagulation, angiogenesis, and regulation of vessel tone and permeability. In this issue of the JCI, Liu et al. provide data that suggest a protective role for kallikrein in animal models of anti-glomerular basement membrane(GBM) antibody-induced nephritis, an experimental model of Goodpasture disease (see the related article beginning on page 911). Furthermore, human systemic lupus erythematosus and lupus nephritis were shown to be associated with kallikrein 1 (KLK1) and the KLK3 promoter. The authors suggest that kallikrein genes are involved in the development of SLE and lupus nephritis and may exert a renoprotective role. It is possible, however, that the kallikrein-kinin system may play dual roles: protecting the kidney against ischemia and interstitial fibrosis while also mediating vasodilation, inflammation, and activation of the innate immune response.

Figure 1. Simplified overview of the kallikrein-kinin system.

Kallikreins originate from prekallikrein, which is cleaved to form kallikrein after being activated by factor XIIa (Hageman factor). Kallikreins are enzymes that cleave kininogens (proteins derived mainly from α₂-globulins) into peptides called kinins. In turn, kinins may be cleaved by kininases to form inactive final products or may bind to their receptors and exert pharmacological activity.

Figure 2. The main mechanisms mediating kidney damage in lupus nephritis.

SLE is characterized by an accumulation of apoptotic material due to its poor clearance (9) (i). This leads to an immune response against chromatin (ii) and to increased expression and binding of apoptotic-chromatin antigens to kidney glomerular structures (iii). Antibodies against apoptotic-chromatin antigens (in particular anti-dsDNA and anti-nucleosome antibodies) may form immune complexes in the kidney with their specific planted antigens or may be entrapped on glomerular structures as immune complexes preformed in the circulation (iv). Immune complex deposition/formation eventually leads to immune-mediated tissue inflammation and damage (v). Local factors may also increase the susceptibility of renal tissue to damage (vi): Chromatin antigens may accumulate in the kidney tissue because of reduced DNAse-mediated chromatin degradation (11), and immune-mediated inflammation may itself increase vessel permeability, consequently increasing diffusion of the autoantigens themselves and of the soluble and cellular mediators of the autoimmune response. In this context, the lack of the potentially protective effect of kinins may represent an additional mechanism contributing to renal tissue damage. Ag, antigen.