Gene may stop diabetic kidney disease progression

New research may help prevent or reduce the progression of diabetic kidney disease, the leading cause of chronic kidney disease worldwide.

The research centers on targeting key cellular signaling between two types of kidney cells, and inducing a certain gene within those processes.

According to the National Kidney Foundation, approximately one in seven adults in the United States has kidney disease, or more than 35 million people. As many as one-third of all Americans with diabetes has kidney disease.

Nephrology researchers have yet to create a therapeutic approach to reverse or prevent the progression of diabetic kidney disease (DKD).

Sandeep K. Mallipattu and lead author Nehaben A. Gujarati of the Division of Nephrology and Hypertension in the medicine department in the Renaissance School of Medicine at Stony Brook University, are hoping that their murine model is a first step toward a new, more effective therapeutic strategy against DKD.

Their findings appear in Nature Communications.

They used a multi-omics (genome, proteome, etc.) approach, to demonstrate that inducing a human KLF6 transcription factor and targeting the cell signaling between podocyte and proximal tubule cells attenuates podocyte loss, proximal tubule dysfunction, and eventual interstitial fibrosis that occurs in later disease stages.

Podocytes play a pivotal role in regulating glomerular function, the filtering process that removes waste and excess water from the blood and forms urine. Proximal tubule cells, the predominant cell type of the kidney, perform many functions such as reabsorbing water, glucose, and certain proteins from the glomerular filtrate and also maintain electrolyte balance and fluid homeostasis. Both of these kidney cell types are critical to preventing the progression of DKD.

In summary, Mallipattu and Gujarati demonstrated in this DKD model that KLF6 triggers the secretion of Apolipoprotein J (ApoJ) from the podocytes, to prime the proximal tubule cells by activating calcium/calmodulin dependent protein kinase 1D (CaMK1D), thereby preventing mitochondrial injury and halting DKD processes.

“This cell to cell communication through this signaling mechanism in the kidney might serve as a protective mechanism in the early stages of DKD,” says senior author Mallipattu, a professor of medicine and chief of the Division of Nephrology and Hypertension.

This study involved a combination of murine models, human cells, and tissue from human kidney biopsies from patients with DKD at various stages.

“In combination, findings from these studies highlight that targeting podocyte-proximal tubule signaling by enhancing Apolipoprotein J-CaMK1D could prove to be a therapeutic strategy in slowing down or perhaps event preventing DKD,” adds Mallipattu.

Gujarati and Mallipattu will continue to test this approach to treating DKD. Their next step in the research is to determine whether pharmacological approaches to activate this signaling pathway in the kidney could prevent individuals with diabetes from developing DKD.

The research was funded in part from the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases and the Dialysis Clinic, Inc.

Source: Stony Brook University

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