TY - JOUR
T1 - Metabolic Analysis and Renal Protective Effects of Linagliptin and Empagliflozin in Alport Syndrome
AU - Ge, Mengyuan
AU - Molina, Judith
AU - Tamayo, Ian
AU - Zhang, Guanshi
AU - Kim, Jin Ju
AU - Njeim, Rachel
AU - Fontanesi, Flavia
AU - Pieper, Michael Paul
AU - Merscher, Sandra
AU - Sharma, Kumar
AU - Fornoni, Alessia
N1 - Publisher Copyright:
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
PY - 2024/7/1
Y1 - 2024/7/1
N2 - 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.
AB - 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.
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U2 - 10.34067/KID.0000000000000472
DO - 10.34067/KID.0000000000000472
M3 - Article
C2 - 38781016
AN - SCOPUS:85199813735
SN - 2641-7650
VL - 5
SP - 1002
EP - 1011
JO - Kidney360
JF - Kidney360
IS - 7
ER -