DOI: 10.1097/imna-d-26-00003 ISSN: 2773-0395

ASK1 Deficiency in Podocytes Reduces Glomerular Macrophages, but not Albuminuria or Glomerulosclerosis, in Early Type 1 Diabetic Kidney Disease

Natasha de Zoysa, Frank Y Ma, Elyce Ozols, Luise A Cullen-McEwen, John F Bertram, David J Nikolic-Paterson, Gregory H Tesch
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Background:

ASK1/p38 MAPK signaling promotes glomerular and tubulointerstitial injury in experimental models of acute and chronic kidney disease. In particular, ASK1 inhibitor treatment protects against albuminuria, podocyte loss, and glomerulosclerosis in models of diabetic kidney disease. Furthermore, p38 MAPK activation in podocytes has been demonstrated in both human and experimental diabetic kidney disease (DKD), suggesting a role of ASK1 signaling in podocyte injury. To investigate this hypothesis, we examined mice with conditional ASK1 gene deletion in podocytes ( ASK1 fl/fl Pod Cre ).

Methods:

DKD was induced by low-dose streptozotocin injections in ASK1 fl/fl Pod Cre mice and ASK1 fl/fl littermate controls, which were euthanized 24 weeks later.

Results:

Efficient ASK1 deletion was confirmed in isolated podocytes. ASK1 and activated (phosphorylated) p38 MAPK were detected in podocytes in diabetic ASK1 fl/fl mice but were absent in diabetic ASK1 fl/fl Pod Cre mice. Urine albumin excretion, glomerular collagen IV deposition, and glomerular accumulation of CD68 + macrophages were all significantly increased in diabetic ASK1 fl/fl mice compared with nondiabetic controls, although podocyte number and density were unchanged. Diabetic ASK1 fl/fl Pod Cre mice exhibited a partial reduction in glomerular accumulation of CD68 + macrophages but were not protected against albuminuria or increased glomerular collagen IV deposition. Podocyte number and density were also unchanged in diabetic ASK1 fl/fl Pod Cre mice.

Conclusion:

Podocyte ASK1/p38 MAPK signaling promotes glomerular macrophage accumulation but does not influence albuminuria or glomerulosclerosis in a model of early DKD.

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