Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy

Abstract

Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow–derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.

Innate immunity in diabetes and diabetic nephropathy

“…Mice with specific non-myeloid derived cell Nlrp3 deficiency, however, were protected against diabetic nephropathy despite transplantation of wild-type bone marrow 158 .…”

“…In diabetic nephropathy, hyperuricaemia is a strong inducer of NLRP3 and IL1 production, which contributes to the progression of disease 158 , and uric acid-lowering agents may demonstrate the therapeutic potential against diabetic nephropathy 156,157 . Hyperglycaemia induced the expression of thioredoxin-interacting protein (TXNIP), an inhibitor of thioredoxin, which activates the gp91 (phox), a subunit of NADPH oxidase, and NLRP3 159 .…”

“…In cultured podocytes, inhibition of NADPH oxidase abrogates NALP3 inflammasome activation and IL1β production, and eventually protects podocytes from high glucose-induced injury 159 . Mitochondrial reactive oxygen species (ROS) activate NLRP3 inflammasomes under conditions of high glucose or advanced glycation end-product stressed podocytes 158 . ASC is a component of NLRP3 inflammasome and shRNA-transfection of Asc in mice on a high fat diet attenuates proteinuria, albuminuria, foot process effacement of podocytes and loss of podocyte slit diaphragm molecules 175 .…”

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

“…6,7 Inflammasome activation has recently been associated and mechanistically linked with dNP. 3 Whether inhibition of caspases using small molecules may be a feasible therapeutic approach and whether such an approach should target caspase-3 and apoptosis remains unknown.…”

“…Conceptually, apoptosis, a caspase-3-dependent immunologically and inflammatorily silent form of cell death, is less likely than celldeath forms associated with inflammation to contribute to the manifestation of dNP, because dNP is closely linked with sterile inflammation. 3,4 Clarifying the functional relevance of apoptosis and other cell-death forms in dNP may be of translational relevance, because several pharmaceutical approaches to target proapoptotic pathways are available or being investigated. 5 Pyroptosis, for example, is a cell-death form associated with inflammation that results from unfettered inflammasome activation, and therapies restricting inflammasome activity are clinically used.…”