Interleukin-1β Inhibition for Chronic Kidney Disease in Obese Mice With Type 2 Diabetes

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.

Glucose Induces IL-1α-Dependent Inflammation and Extracellular Matrix Proteins Expression and Deposition in Renal Tubular Epithelial Cells in Diabetic Kidney Disease

“…Total RNA was extracted from paraffin-embedded sections, and IL-1 gene expressions between the healthy control (HC) group and DN tissues were compared ( Figure 1A ). Surprisingly, in contrast to a recent report ( 20 ), we could not observe a substantial IL-1β expression in any of the biopsies normalized gene expression comparing DN to HC. Remarkably, a dramatic IL-1α expression could be seen, especially in DN samples, which shows significant tubulointerstitial injury followed by elevation in IL-1Ra ( Figure 1A ).…”

“…Although IL-1α showed strong cytoplasmic expression, especially in dilated atrophic renal proximal tubule cells of DN patients, no IL-1β could be detected in any of the kidney DN samples ( Figure 1C ). Remarkably, in agreement with our data, the recent report by Lei et al ( 20 ) also shows extensive IL-1α immunostaining in biopsies of human DN of the tubular cells with marginal positive glomeruli staining present in the control samples. Importantly, IL-1α and not IL-1β transcript levels were shown to be elevated in a mouse model of diabetes mellitus type 2 significantly above wild-type (WT) mice, supporting the notion that IL-1β transcript and protein expression in the kidney predominately originate from infiltrating immune cells and not from any of the kidney cells ( 20 ).…”

Empagliflozin Inhibits Basal and IL-1β-Mediated MCP-1/CCL2 and Endothelin-1 Expression in Human Proximal Tubular Cells

“…IL-1β antagonism reduces systemic inflammation in type II diabetic patients [35] and had beneficial effects on diabetes-related CKD in murine studies [36,37]. Most recently, the inhibition of IL-1β by using a monoclonal antibody in diabetic db/db mice with progressive kidney disease was demonstrated to reduce the expression of renal damage markers and to attenuate GFR decline [38]. These findings indicate that IL-1β antagonism might be a therapeutic option in diabetic and non-diabetic CKD and emphasize the relevance of our present results showing an inhibitory effect of Empa on IL-1β-mediated gene expression in HPTCs.…”

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

“…Therapeutics approaches have targeted IL-1β in diabetes. For example, in uninephrectomized db/db mice, an anti-IL-1β antibody reduced fibrosis, podocyte injury, and progressive decline of eGFR [132]. In the clinical field, the studies analyzed the role of IL-1β blockade in renal disease are not conclusive.…”