Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney.

Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney. Am J Physiol Renal Physiol. 2020 Mar 02;: Authors: Hodrea J, Balogh DB, Hosszu A, Lenart L, Besztercei B, Koszegi S, Sparding N, Genovese F, Wagner LJ, Szabó AJ, Fekete A Abstract Diabetic kidney disease is a worldwide epidemic and therapies are incomplete. Clinical data suggest that improved renal outcomes by SGLT2i are partly beyond their antihyperglycemic effects, however the mechanisms are still elusive. Here we investigated the effect of SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 weeks with a DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia cells were kept in 1% O2 for 2 hours. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (KIM-1, NGAL) and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the HIF pathway. DAPA alone was as effective as combined treatment with losartan in all...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research