PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection

Abstract

The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischemia. Indeed, acute kidney injury (AKI) affects 3% of all hospitalized patients.1,2 Here we show that the mitochondrial biogenesis regulator, PGC1α,3,4 is a pivotal determinant of renal recovery from injury by regulating NAD biosynthesis. Following renal ischemia, PGC1α−/− mice developed local deficiency of the NAD precursor niacinamide (Nam), marked fat accumulation, and failure to re-establish normal function. Remarkably, exogenous Nam improved local NAD levels, fat accumulation, and renal function in post-ischemic PGC1α−/− mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulated the effects of Nam supplementation, including more local NAD and less fat accumulation with better renal function after ischemia. PGC1α coordinately upregulated the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuated the de novo pathway. Nam enhanced NAD via the enzyme NAMPT and augmented production of the fat breakdown product beta-hydroxybutyrate (β-OHB), leading to increased prostaglandin PGE2, a secreted autocoid that maintains renal function.5 Nam treatment reversed established ischemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of β-OHB signaling or prostaglandins similarly abolished PGC1α-dependent renoprotection. Given the importance of mitochondrial health in aging and the function of metabolically active organs, the results implicate Nam and NAD as key effectors for achieving PGC1α-dependent stress resistance.

Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy

“…Our results reinforce the importance of mitochondria as one of the key components of this complex and a major part of the multifactorial complications of diabetes (9,10,38,39). This study underscores previous observations by our group and others that improving mitochondrial function, by targeting mitochondrial dynamics, activity, or numbers, is renoprotective in different models of kidney injury, including DN (12,(40)(41)(42)(43)(44)(45)(46)(47)(48). We provide evidence that PGC-1α is a mechanistic target of Tug1 in podocytes in the kidney, through which Tug1 regulates mitochondrial bioenergetics.…”

PPARγ-Coactivator-1α, Nicotinamide Adenine Dinucleotide and Renal Stress Resistance

“…During experimental and human AKI, renal PGC1α expression falls [17,25,29]. This change in expression does not appear to drive the mitochondrial pathology of AKI per se, but does appear to impair the cell’s ability to respond to mitochondrial injury.…”

Mitochondria–Power Players in Kidney Function?

“…In the paper by Tran et al there is accumulation of FAs in kidneys damaged by ischaemia, which is exacerbated with PGC1/ knockout and reversed by restoring cellular NAD concentrations [2]. Although the authors suggest that the accumulation of kidney free FAs is pathological, some studies suggest a contrasting argument.…”

“…An elegant study in the journal Nature has highlighted the intimate relationship between cellular maintenance of the mitochondrial fuel precursor NAD/NADH [1], mitochondrial health, and kidney function [2]. Acute kidney injury affects about 3% of all hospitalised patients, particularly after major surgical procedures, including cardiac bypass and blood loss.…”