Role of Dipeptidyl Peptidase 4 and Effects of a Western Diet in Renal Sodium Transport and Tubular Injury
Authors: Allada Rohit , Ren Jing , Restrepo Ricardo , Nistala Ravi 
Published: May 2022

The protein dipeptidyl peptidase 4 (DPP4) is a target in the management of Type 2 diabetes mellitus (T2DM) and inhibition decreases albuminuria in humans with high cardiovascular risk such as subjects with T2DM, obesity/insulin resistance and hypertension. Our laboratory and others have shown that inhibition or genetic deletion of DPP4 has nephroprotective effects not only in rodent models of DM/insulin resistance but also obesity and hypertension. In addition, all three conditions with high cardiovascular risk are characterized by sodium retention. Recent data shows that DPP4 may affect sodium transport within the kidney via binding to sodium/hydrogen exchanger 3 (NHE3) and translocating to the villi in the brush border of the tubules. We have observed increased tubular damage and sodium uptake in a high fat/high sugar diet (Western diet) model of obesity in the setting of increased DPP4 activity. Therefore, we hypothesized that reduction/suppression of DPP4 expression/signaling and/or activity may lead to decreased sodium retention in the kidney in the obese mice.

Methods

Proximal tubule specific DPP4fl/fl;SGLT2Cre+ (PT DPP4KO) and DPP4fl/fl;SGLT2Cre‐ (PT DPP4WT) mice were fed a WD and control chow (CD) till sacrifice (18 to 27 mths). 24 hour urine collection and measurement of sodium excretion was done in these mice while on the diets. Gene and protein expression of transporters (sodium and water) was quantitated. Whole body DPP4‐/‐ (DPP4KO) and DPP4+/+ (DPP4WT) were on control chow diet and placed in metabolic cages for sodium balance studies. On days 3 and 4, mice were given 1% NaCl in drinking water. Daily mice weight, food and water consumption and urinary excretion of sodium and potassium and creatinine were measured.

Results

The PT DPP4WT mice showed a much reduced 24 hour excretion of sodium compared to the PT DPP4KO mice (p<0.05) which was consistent with data from DPP4WT and DPP4KO mice on WD (unpublished) as well as data from DPP4 inhibitor treated mice (Nistala et al, Endocrinology 2014 Jun;155(6):2266‐76). Urinary sodium excretion was increased in both DPP4WT and DPP4KO mice on 1% NaCl in drinking water but the excretion was significantly increased in DPP4KO mice compared to DPP4WT mice. Excretion of glucose and other electrolytes reached a peak on the 3rd day and tapered off slightly on the 4th day. The increased excretion of sodium and water as well as slight reduction in food intake, led to gradual decrease in weight of the animals (~1gm) which was not significant between the WT and KO groups. The gene expression of many sodium and water transporters increased including NHE3, ENaCγ and AQP1/2 in the PT DPP4WT mice, while expression was reduced in the PT DPP4KO mice fed a Western Diet. The protein expression of NHE3 increased in WT mice and was suppressed in KO mice.

Conclusion

DPP4 expression was increased in PT DPP4WT mice fed a Western diet and reduced in the KO mice and this correlated with increased expression of NHE3 in the WT and reduction in KO mice. In the whole body DPP4KO mice, lack of DPP4 led to greater increase in sodium and water excretion. Taken together, proximal tubule DPP4 may be involved in regulating sodium and water homeostasis in CD and WD‐fed mice. Sodium excretion under conditions of low salt diet will help establish DPP4's role in sodium homeostasis.