Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Abstract

Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1b), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucosestressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.

Expression of inflammasome complex mRNA and its targeted microRNA in type 2 diabetes mellitus: A possible predictor of the severity of diabetic nephropathy

“…These findings suggest that CASP1 may be a better explanatory marker for an adverse prognosis of DN. Activation of NLRP3 and caspase 1 may have led to maturation of inflammatory cytokines and induction of pyroptosis in an animal model . Pyroptosis in DK has been suggested to indicate an adverse prognosis of DN, at least in animal models, and the present observation replicates the phenomenon in humans.…”

Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

“…5a). We therefore turned our attention to inflammatory cell death mechanisms as it has been shown that defect in non-inflammatory cell death can shift towards inflammatory cell death pathways including pyroptosis 25,26 . We found that cleaved caspase1, the key player in pyroptosis, was increased in APOL1 transfected cells.…”

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

“…Those that do, obtain inconclusive results. [60][61][62][63][64] Convincing evidence was demonstrated for renal fibroblasts. 65 Others conclude on inflammasome activation from immunostaining or transcript analysis, [66][67][68] which is inadequate given the post-transcriptional nature of inflammasome activity.…”

“…21 The published data become conflicting when reporting pro-IL-1b processing and IL-1b release from renal parenchymal cells. 60,61 Only a few studies demonstrate the secretion of mature IL-1b from immune cell-free tissue specimens or from nonimmune renal cell cultures by ELISA and western blot. Those that do, obtain inconclusive results.…”

“…61 Their analysis also included bone marrow transplant studies documenting a significant contribution of NLRP3-mediated caspase-1 activation inside nonimmune cells to podocyte loss, albuminuria, and glomerulosclerosis. 60,61 As their experiments involved conventional knockout mice it remains unclear if this relates to NLRP3 in nonimmune cells in-or outside the kidney. Reports on other CKD models such as hypertensive nephrosclerosis, Western diet-, toxin-, or oxalate crystal-induced nephropathy or ureter obstruction were only conducted using Nlrp3-deficient mice, but consistently displayed a protected phenotype (Table 3).…”