ASK1 limits kidney glucose reabsorption, growth, and mid-late proximal tubule KIM-1 induction when diabetes and Western diet are combined with SGLT2 inhibition

Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor (ASK1i) that attenuated the decline in creatinine-based estimated GFR in humans with type 2 diabetes and kidney disease but increased the rate of acute kidney injury. This study explored the individual and combined kidney effects of selonsertib and the antihyperglycemic sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in Western diet-fed male Akita mice, a murine model of early type 1 diabetes mellitus showing signs of systemic but no kidney inflammation. ASK1i reduced elevated plasma levels of proinflammatory cytokines/chemokines (IL-6, MCP1/CCL2, KC/CXCL1, and IP-10/CXCL10) without significantly changing hyperglycemia, glomerular hyperfiltration, and albuminuria or affecting the blood glucose and glomerular hyperfiltration-lowering effect of SGLT2i. A potential sign of tubular stress, SGLT2i modestly upregulated kidney cortex transcription of proinflammatory and profibrotic genes and distal tubule injury marker Ngal. Adding ASK1i to SGLT2i lowered the transcription of many of these genes, including Ngal. However, ASK1i enhanced kidney glucose reabsorption independent of SGLT2i, and combined ASK1i + SGLT2i increased kidney weight by 30%. This was associated with and positively correlated with the upregulation of the tubular stress/injury marker KIM-1, primarily in the mid-to-late proximal tubule. Combined ASK1i + SGLT2i increased the tubular injury score but not signs of kidney inflammation or fibrosis beyond a robust increase in kidney mRNA expression of Il6, Ccl2 (Mcp1), and Timp1, associated with increased plasma IL-6 levels. The data support the hypothesis that housekeeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in the mid-to-late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition.<b>NEW & NOTEWORTHY</b> Selonsertib is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor that attenuated creatinine-based eGFR decline in humans with type 2 diabetes and kidney disease but increased acute kidney injury rates. Here, we report evidence in a murine model of early type 1 diabetes mellitus that housekeeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in the mid-to-late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition.