SGLT2 Inhibition Promotes Intrinsic Kidney Regeneration by Cells of the Renin Lineage

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Background: With chronic kidney disease (CKD) prevalence rapidly increasing, the need for novel therapies rises. Sodium glucose co-transporter-2 (SGLT2) inhibitors were initially developed to treat hyperglycemia in diabetes type 2. Clinical trials with the SGLT2 inhibitor Empagliflozin (EMPA) revealed a remarkable renal protective effect in patients with (non-) diabetic CKD, but the molecular mechanism behind this remains to be clarified. Interestingly, the cells of renin lineage (CoRL) in the juxtaglomerular apparatus have been demonstrated to harbor a progenitor potential. Upon injury or aging, CoRL are able to migrate into the glomerular tuft where they start expressing different glomerular cell markers in several CKD mouse models. Considering that EMPA treatment affects renin plasma levels and electrolyte balance in patients, we hypothesized that SGLT2 inhibition might have an effect on CoRL-induced glomerular regeneration. Methods: Experiments were performed in a Ren1cre;tdTomato lineage-trace mouse strain that expresses a tomato fluorescent label in cells derived from renin lineage. Two kidney injury models were applied; bilateral ischemia reperfusion injury (bIRI) and 5/6 nephrectomy (5/6NTx). EMPA (10 mg/kg) was administered daily by oral gavage for 14 days. Subsequently, kidneys were harvested for histological analysis. Results: In both the bIRI and 5/6NTx model, EMPA intake led to an increase (>2 fold) of CoRL found in intraglomerular regions compared to vehicle control. These CoRL differentiated selectively towards different glomerular cell types per model: bIRI combined with EMPA administration resulted in an increase of claudin- (10 fold) and integrin-α8- (1.5 fold) tomato double positive cells, suggesting favored differentiation from CoRL to respectively a parietal epithelial or mesangial cell type. In contrast, in the EMPA treated 5/6NTx model, an increase (1.5 fold) in tomato-podocyn double positive cells was observed, implying more restocking of podocytes by CoRL in this model. Conclusions: SGLT2 inhibition by EMPA treatment leads to increased CoRLmediated intrinsic regeneration potential and provides the kidney with different replenished cell types in different kidney disease models. Our findings demonstrate a novel mechanism via which SGLT2 inhibition might protect against kidney injury. Funding: Commercial Support - Boehringer Ingelheim

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