Metabolic Analysis and Renal Protective Effects of Linagliptin and Empagliflozin in Alport Syndrome

Abstract

Key Points Linagliptin reduces kidney function decline and extends lifespan in Alport syndrome mice.Inhibiting the generation of glucose metabolites could serve as a potential therapeutic strategy for the treatment of Alport syndrome. Background We previously demonstrated that empagliflozin (Empa), a sodium-glucose cotransporter-2 inhibitor, reduces intrarenal lipid accumulation and slows kidney function decline in experimental Alport syndrome (AS). In this study, we aimed to evaluate the renal protective benefits of linagliptin (Lina), a dipeptidyl peptidase-4 inhibitor in AS, and compare it with Empa. Methods Metabolite distribution in kidney cortices was assessed using mass spectrometry imaging. We examined albuminuria and histological changes in kidneys from AS mice treated with Lina and/or Empa or vehicle. Results Several metabolites, including adrenic acid and glucose, were increased in renal cortices of AS mice compared with wild-type (WT) mice, whereas eicosapentaenoic acid levels were decreased. In addition, a redistribution of adrenic acid from the glomerular compartment in WT mice to the tubulointerstitial compartment in AS mice was observed. Both Lina and Empa treatments were found to reduce albuminuria to extend the survival of AS mice for about 10 days and to decrease glomerulosclerosis and tubulointerstitial fibrosis compared with WT mice. There were no significant differences with regard to the renal phenotype observed between Empa- and Lina-treated AS mice, and the combination of Lina and Empa was not superior to individual treatments. In vitro experiments revealed that dipeptidyl peptidase-4 is expressed in podocytes and tubular cells derived from both AS and WT mice. Differently from what we have reported for Empa, Lina treatment was found to reduce glucose-driven respiration in AS tubular cells but not in AS podocytes. Conclusions Renal expression patterns and spatial distribution of several metabolites differ in AS compared with WT mice. Although Lina and Empa treatments similarly partially slow the progression of kidney disease in AS, the metabolic mechanisms conferring the protective effect may be different.