Treatment of Diabetic Kidney Disease: Current and Future

Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatments is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2–related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.

The role of oxidative stress and hypoxia in renal disease

Oxygen is required to sustain aerobic organisms. Reactive oxygen species (ROS) are constantly released during mitochondrial oxygen consumption for energy production. Any imbalance between ROS production and its scavenger system induces oxidative stress. Oxidative stress, a critical contributor to tissue damage, is well-known to be associated with various diseases. The kidney is susceptible to hypoxia, and renal hypoxia is a common final pathway to end stage kidney disease, regardless of the underlying cause. Renal hypoxia aggravates oxidative stress, and elevated oxidative stress, in turn, exacerbates renal hypoxia. Oxidative stress is also enhanced in chronic kidney disease, especially diabetic kidney disease, through various mechanisms. Thus, the vicious cycle between oxidative stress and renal hypoxia critically contributes to the progression of renal injury. This review examines recent evidence connecting chronic hypoxia and oxidative stress in renal disease and subsequently describes several promising therapeutic approaches against oxidative stress.

The role of renal proximal tubule transport in the regulation of blood pressure

The electrogenic sodium/bicarbonate cotransporter 1 (NBCe1) on the basolateral side of the renal proximal tubule plays a pivotal role in systemic acid-base homeostasis. Mutations in the gene encoding NBCe1 cause severe proximal renal tubular acidosis accompanied by other extrarenal symptoms. The proximal tubule reabsorbs most of the sodium filtered in the glomerulus, contributing to the regulation of plasma volume and blood pressure. NBCe1 and other sodium transporters in the proximal tubule are regulated by hormones, such as angiotensin II and insulin. Angiotensin II is probably the most important stimulator of sodium reabsorption. Proximal tubule AT(1A) receptor is crucial for the systemic pressor effect of angiotensin II. In rodents and rabbits, the effect on proximal tubule NBCe1 is biphasic; at low concentration, angiotensin II stimulates NBCe1 via PKC/cAMP/ERK, whereas at high concentration, it inhibits NBCe1 via NO/cGMP/cGKII. In contrast, in human proximal tubule, angiotensin II has a dose-dependent monophasic stimulatory effect via NO/cGMP/ERK. Insulin stimulates the proximal tubule sodium transport, which is IRS2-dependent. We found that in insulin resistance and overt diabetic nephropathy, stimulatory effect of insulin on proximal tubule transport was preserved. Our results suggest that the preserved stimulation of the proximal tubule enhances sodium reabsorption, contributing to the pathogenesis of hypertension with metabolic syndrome. We describe recent findings regarding the role of proximal tubule transport in the regulation of blood pressure, focusing on the effects of angiotensin II and insulin.