Abstract
Inflammasome-driven release of interleukin(IL)-1β is a central element of many forms of sterile inflammation and has been evident to promote the onset and progression of diabetic kidney disease. We microdissected glomerular and tubulointerstitial samples from kidney biopsies of patients with diabetic kidney disease and found expression of IL-1β mRNA. Immunostaining of such kidney biopsies across a broad spectrum of diabetic kidney disease stages revealed IL-1β positivity in a small subset of infiltrating immune cell. Thus, we speculated on a potential of IL-1β as a therapeutic target and neutralizing the biological effects of murine IL-1β with a novel monoclonal antibody in uninephrectomized diabetic db/db mice with progressive type 2 diabetes- and obesity-related single nephron hyperfiltration, podocyte loss, proteinuria, and progressive decline of total glomerular filtration rate (GFR). At 18 weeks albuminuric mice were randomized to intraperitoneal injections with either anti-IL-1β or control IgG once weekly for 8 weeks. During this period, anti-IL-1β IgG had no effect on food or fluid intake, body weight, and fasting glucose levels. At week 26, anti-IL-1β IgG had reduced renal mRNA expression of kidney injury markers (Ngal) and fibrosis (Col1, a-Sma), significantly attenuated the progressive decline of GFR in hyperfiltrating diabetic mice, and preserved podocyte number without affecting albuminuria or indicators of single nephron hyperfiltration. No adverse effect were observed. Thus, IL-1β contributes to the progression of chronic kidney disease in type 2 diabetes and might therefore be a valuable therapeutic target, potentially in combination with drugs with different mechanisms-of-action such as RAS and SGLT2 inhibitors.
Highlights
Type 2 diabetic mellitus (T2DM) is systemic disorder and global health concern
To localize IL-1β protein expression we performed immunostaining on several such diagnostic biopsies from patients with different stages of diabetes-related Chronic kidney disease (CKD) and found IL-1β positivity exclusively localized to few infiltrating mononuclear cells, most likely macrophages, inside glomeruli as well as the tubulointerstitium and in some tubular cells (Figure 1B)
Graphs showed the mean numbers of Wilms Tumor (WT)-1 positive cells in 15-25 glomeruli ± SEM in sections. (H–I) Kidney mRNA expression levels were quantified by real–time RT-PCR. (J) Kidney sections of 26 weeks old mice of all groups were stained for Mac-2 to quantify macrophages per glomerular cross section
Summary
Chronic kidney disease (CKD) is common in T2DM and largely contributes to morbidity and mortality. Diabetic and non-diabetic nephropathies or a combination of both contribute to the progression of CKD in T2DM and all involve a contribution of local and systemic sterile inflammation driving kidney atrophy [1]. Sterile inflammation is a consequence of danger signals released from cells under glycotoxic, oxidative, or other forms of stress activating inflammasomes and other pattern recognition receptors [2, 3]. The NLRP3 inflammasome induces the assembly of IL-1β in Diabetic Kidney Disease several cytosolic proteins leading to activation of caspase-1, which promotes the enzymatic activation and secretion of mature IL-1β [4, 5]. The evidence supporting the mechanistic concept that IL-1β would drive systemic inflammation and vascular injury in diabetes is less consistent [10, 13,14,15,16,17]
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