Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury

Milica Bugarski; Susan Ghazi; Marcello Polesel; Joana R. Martins; Andrew M. Hall

doi:10.1681/ASN.2020071003

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Visual Abstract

Significance Statement

Clinical studies have suggested that metabolic acidosis (MA) aggravates tubular damage in patients with both AKI and CKD, but the mechanisms were unknown. Intravital live cell imaging and other complementary techniques demonstrated in the mouse kidney that MA induces acute changes in the mitochondrial NAD redox state, respiratory chain function, and lipid metabolism, which collectively lead to tubular cell damage. Intravenous injection of bicarbonate increases blood pH and improves tubular function, whereas pretreatment with an NAD precursor is highly protective. Thus, changes in cell metabolism explain the harmful effects of MA on kidney tubules, which therapeutic strategies that are viable in humans can substantially ameliorate.

Abstract

Background The kidney plays an important role in maintaining normal blood pH. Metabolic acidosis (MA) upregulates the pathway that mitochondria in the proximal tubule (PT) use to produce ammonia and bicarbonate from glutamine, and is associated with AKI. However, the extent to which MA causes AKI, and thus whether treating MA would be beneficial, is unclear.

Methods Gavage with ammonium chloride induced acute MA. Multiphoton imaging of mitochondria (NADH/membrane potential) and transport function (dextran/albumin uptake), oxygen consumption rate (OCR) measurements in isolated tubules, histologic analysis, and electron microscopy in fixed tissue, and urinary biomarkers (KIM-1/clara cell 16) assessed tubular cell structure and function in mouse kidney cortex.

Results MA induces an acute change in NAD redox state (toward oxidation) in PT mitochondria, without changing the mitochondrial energization state. This change is associated with a switch toward complex I activity and decreased maximal OCR, and a major alteration in normal lipid metabolism, resulting in marked lipid accumulation in PTs and the formation of large multilamellar bodies. These changes, in turn, lead to acute tubular damage and a severe defect in solute uptake. Increasing blood pH with intravenous bicarbonate substantially improves tubular function, whereas preinjection with the NAD precursor nicotinamide (NAM) is highly protective.

Conclusions MA induces AKI via changes in PT NAD and lipid metabolism, which can be reversed or prevented by treatment strategies that are viable in humans. These findings might also help to explain why MA accelerates decline in function in CKD.

View Full Text

Log in through your institution

Purchase access

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$27.00

You will have access to the article for 24 hours.

If you do not have an account, you will need to create one and you will be asked for your name, email address and other information. Just like commercial web sites, we do need details from you in order to complete your purchase of an article. Select the "Create an Account" link to create your account.

You will then be asked to register a user name, email address and you will need to create a password that is at least eight characters in length. As you move through the registration page, you will have to verify you are a person by completing a Captcha request. Lastly, your first and last name will be required.

Once your information is successfully saved, the system will redisplay the home page of the journal. From there, navigate back to the article to purchase. Select the article and at the bottom of the page, use the credentials you just created to login. The article will be added to your shopping cart. You can continue to navigate across JASN and CJASN adding to your cart from both journals. When you are ready to complete your purchse, select the Shopping Cart from the upper right hand corner of the page and follow the onscreen instructions.