Highlights

·    Diabetic mice treated with NMN for two weeks showed improved kidney structure and function, increasing survival.
·    This treatment paradigm can enhance possibilities for achieving the remission of diabetes-related kidney disorder and other diabetic complications.

Up to 40% of patients with diabetes progress to the deterioration of kidney function (a condition called diabetic nephropathy), the leading cause of kidney (renal) failure. Progression of diabetic nephropathy has been shown to go hand in hand with metabolic abnormalities and the renal dysregulation of NAD+ — a cofactor that enzymes participating in a multitude of critical cell functions including healthspan and lifespan depend on for their function. Nicotinamide mononucleotide (NMN) is the precursor of NAD+, which, in several disease models, researchers have administered with favorable outcomes.

In an article published in the Journal of the American Society of Nephrology, Yasuda and colleagues from Keio University showed long-lasting protection against early diabetic nephropathy by short-term supplementation with NMN in mice. Specifically, two weeks of NMN injection treatment (500 mg/kg) decreased a condition called albuminuria — when kidney damage causes excess buildup of proteins in urine — and survival rates significantly increased. These improvements were accompanied by improvements in the health and form of the kidney’s substructures and specialized cells critical to its filtration function.

“In this study, we, for the first time, observed a long-lasting renoprotective effect by short-term transient NMN treatment on diabetic nephropathy,” concluded the authors. “We provide a proof of concept for transient short-term administration of NMN as an effective treatment for early-stage diabetic nephropathy.”

NMN treatment improves kidney function and survival in diabetic mice

Yasuda and colleagues tested the effects of preemptive short-term treatment with NMN before the onset of albuminuria and assessed the effects up to 20 weeks after the discontinuation of the treatment. NMN treated diabetic mice exhibited lower albuminuria levels than those of the untreated diabetic group at both 10 and 24 weeks of age, which suggests an inhibitory effect of NMN on albuminuria. This effect was sustained even after the termination of the short-term NMN intervention and was still observed even at 30 weeks of age.

The Keio University researchers also evaluated the effect of NMN treatment on the kidneys ability to properly filter substances, which is linked with early phases of kidney disease. To do so, they measured the filtration rate of creatine, which becomes excessive, a state called hyperfiltration, and is indicative of failing kidney function. Although not significant, there was an improvement in hyperfiltration as seen by increased retention of creatine in mice treated with NMN.

In addition, NMN administration improved survival rates, which had not been reported to date. NMN treatment was associated with 15% lower death rates in diabetic mice. This was accompanied with major reductions in gastrointestinal tract perforation — when a hole forms all the way through the stomach, large bowel, or small intestine — which Yasuda and colleagues think could partially explain the survival results.

(Yasuda et al., 2021 | J Am Soc Nephrol) Short-term NMN treatment improves kidney function and overall survival. Urine albumin-creatinine ratio (ACR), indicative of albuminuria — a condition of having too much protein in the urine which results from damage within the kidneys — was measured at 30 weeks of age in the three groups: control (db/m), diabetic (db/db), and NMN treated diabetic (NMN500) mice. (G) Creatine clearance at 10 weeks of age in the three groups. (H) Survival plots for the survivors in the treatment groups.

To understand these kidney protective effects, Yasuda and colleagues looked at the molecular and structural makeup of these mice treated with NMN. Before progression to early stage renal disease, diabetic nephropathy is characterized by an enlargement in substructures of the kidney called glomeruli responsible for filtering blood and the alteration of specialized cells within the glomerulus called podocytes, which play an active role in preventing plasma proteins from entering the urine filtrate.

What the Keio University researchers found was that NMN treatment ameliorated swelling and enlargement of the glomeruli in diabetic mice. Yasuda and colleagues also observed an improvement in the quantity of podocyte foot processes, substructures that form filtration barriers that help maintain normal renal function. Damage in this area has been implicated in glomerular disease.

(Yasuda et al., 2021 | J Am Soc Nephrol) Short-term NMN treatment ameliorated histologic changes in diabetic nephropathy. (C) Glycogen deposits in the kidney, quantified by the positivity of periodic acid–Schiff (PAS) in the glomerulus. (G) The density of podocyte foot processes in the kidney, indicative of renal integrity and function.

“This study provides evidence of legacy effects of NMN treatment and that short-term NMN supplementation suppresses the long-term progression of diabetic nephropathy,” proposed Yasuda and colleagues. “These findings indicate NMN is a potential preventive treatment in diabetic nephropathy.”