TY - JOUR

T1 - Mitochondrion-driven nephroprotective mechanisms of novel glucose lowering medications

AU - Afsar, Baris

AU - Hornum, Mads

AU - Afsar, Rengin Elsurer

AU - Ertuglu, Lale A.

AU - Ortiz, Alberto

AU - Covic, Adrian

AU - van Raalte, Daniel H.

AU - Cherney, David Z.I.

AU - Kanbay, Mehmet

PY - 2021

Y1 - 2021

N2 - Therapy for diabetic kidney disease (DKD) is undergoing a revolution with the realization that some glucose-lowering drugs have nephroprotective actions that may be intrinsic to the drugs and not dependent on the impact on diabetes control, as demonstrated with the sodium glucose co-transporter-2 (SGLT-2) inhibitors. Mitochondria are a critical factor required for the maintenance of kidney function, given its high energy demanding profile, with extensive use of adenosine triphosphate (ATP). Consequently, deficiency of the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1α predisposes to kidney disease. Perhaps as a result of key role of mitochondria in fundamental cellular functions, mitochondrial dysfunction may play a role in the pathogenesis of common conditions such as DKD. Finding pharmacological agents to influence this pathway could therefore lead to early implementation of therapy. Importantly, glucose-lowering drugs such as glucagon-like peptide-1 receptor activators and SGLT2 inhibitors have kidney and/or cardioprotective actions in patients with diabetes. Accumulating evidence from preclinical studies has suggested a protective effect of these drugs that is in part mediated by normalizing mitochondrial function. We now critically review this evidence and discuss studies needed to confirm mitochondrial protective benefits across a range of clinical studies.

AB - Therapy for diabetic kidney disease (DKD) is undergoing a revolution with the realization that some glucose-lowering drugs have nephroprotective actions that may be intrinsic to the drugs and not dependent on the impact on diabetes control, as demonstrated with the sodium glucose co-transporter-2 (SGLT-2) inhibitors. Mitochondria are a critical factor required for the maintenance of kidney function, given its high energy demanding profile, with extensive use of adenosine triphosphate (ATP). Consequently, deficiency of the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1α predisposes to kidney disease. Perhaps as a result of key role of mitochondria in fundamental cellular functions, mitochondrial dysfunction may play a role in the pathogenesis of common conditions such as DKD. Finding pharmacological agents to influence this pathway could therefore lead to early implementation of therapy. Importantly, glucose-lowering drugs such as glucagon-like peptide-1 receptor activators and SGLT2 inhibitors have kidney and/or cardioprotective actions in patients with diabetes. Accumulating evidence from preclinical studies has suggested a protective effect of these drugs that is in part mediated by normalizing mitochondrial function. We now critically review this evidence and discuss studies needed to confirm mitochondrial protective benefits across a range of clinical studies.

KW - Diabetes

KW - Diabetic kidney disease

KW - GLP-1 receptor activators

KW - Mitochondria

KW - Organ protection

KW - SGLT2 inhibitors

U2 - 10.1016/j.mito.2021.02.016

DO - 10.1016/j.mito.2021.02.016

M3 - Review

C2 - 33677060

AN - SCOPUS:85102243295

VL - 58

SP - 72

EP - 82

JO - Mitochondrion

JF - Mitochondrion

SN - 1567-7249

ER -