Diabetes is the leading driver of kidney disease, a potentially fatal condition affecting millions people wordlwide. Diabetes damages the kidneys by preventing the organs from effectively filtering wastes and excess fluids from the body. Because symptoms such as nausea, vomiting, sleep disturbances and swollen limbs are common and nonspecific to kidney disease, most people don’t realize they have it until irreparable organ damage occurs. Diabetic kidney disease occurs in about 40% of patients with type 2 diabetes, leading to kidney failure, cardiovascular disease and premature death. No cure exists, and current treatments for end-stage disease primarily are limited to dialysis and kidney transplant. In pursuit of improved drug therapies for this condition, a mouse study led by Washington University School of Medicine in St. Louis suggests that combining SGLT2 inhibitors with older diabetes drugs may help to slow the progression of diabetic kidney disease (CKD/DKD).
Commonly prescribed SGLT2 inhibitors, a newer class of diabetes medications that lowers blood sugar, include empagliflozin (Jardiance), dapagliflozin (Farxiga) and canagliflozin (Invokana). SGLT2 inhibitors (technically known as sodium-glucose cotransporter-2 inhibitors) prompt the kidneys to eliminate excess sugar from the blood, and such sugar is lost through urine SGLT2 inhibitors have had remarkably positive effects on kidney disease in diabetes, the best effects that we have seen in decades. Yet scientists have not understood specifically how and why these drugs work so well. Most patients with type 2 diabetes are prescribed only a single drug, but the study’s results suggest that combination therapies may be more effective because the different drug classes target different cell types in the kidney. Studying mice that had developed diabetic kidney disease, the researchers analyzed how mouse kidneys respond to five diabetes treatment regimens prescribed to patients.
The team examined responses using single-cell RNA sequencing, which allowed them to identify changes in the kidneys at the cellular and molecular level to the different treatments. Understanding such interworkings can help researchers target specific cells to improve drug therapies. They studied the effects of individual classes of drugs and combinations of drugs, focusing on three classes of drugs: SGLT2 inhibitors; angiotensin converting enzyme inhibitors (ACE inhibitors) such as Fosinopril and Lisinopril; and Thiazolidinediones (TZD, also known as insulin sensitizers). Pioglitazone and Rosiglitazone are two common drugs of this class. The study found that the combination of SGLT2 inhibitors with Lisinopril had better protective effects on the kidney than any of the single therapies alone. The researchers also noted that SGLT2 inhibitors seemed to trick the kidney into activating a starvation response, similar to how the body slows down its metabolism when fasting for prolonged periods.
A mechanism of this kind is also implemented by the very famous metformin, which is widely used for the management of diabetes and the prevention of its complications. However, its mechanism of action is different from that of SGLT2 inhibitors: in fact, it acts directly on mitochondrial energy and on the enzymatic responses downstream of this. The SGLT2 inhibitors, on the other hand, do not allow glucose but also sodium to enter the cells. The SGLT2 co-transporters, indeed, are electrogenic and carry a glucose molecule along with sodium ions into the cell, which creates an electrical potential difference and an osmotic gradient that draws water. The SGLT2 inhibitors, therefore, protect the kidney cells avoiding an excessive cellular load of glucose (which would cause oxidative stress) and sodium ions (which would lead to osmotic and electrochemical imbalance). This may reduce overall energy consumption in the kidney, allowing it to work more efficiently and placing less of a burden on it long term.
It is possible that this category of drugs also act by activating other protective cellular signaling or by arriving at signal transduction sub-branches dependent on glucose and ionic currents of cellular sodium and calcium. For example, in a model of renal damage induced by radio-contrast drug, dapagliflozine attenuates cell damage leading to the activation of the HIF-1 (hypoxia protection response) and NF-kB (cell death protection) pathways. This would possibly explaining why this class of drugs is more effective than metformin and glitazones alone. Scientists deem that future observational studies in people taking combination therapies should provide further evidence. The whole research appear in the June 15 number of the journal Cell Metabolism.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Advised in this website
Wu H et al. Cell Metabolism 2022
van Ruiten CC et al. Eur J Intern Med. 2022 Jun; 100:13-20.
Dabravolski SA et al. Int J Mol Sci. 2022 May; 23(10):5371.
Huang X et al. J Cardiovasc Pharmacol. 2022; 79(6):904-13.
Dott. Gianfrancesco Cormaci
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