This study shows that podocyte-derived FGF4 is reduced in DKD and that recombinant FGF4 preserves podocyte survival and glomerular function in diabetic models via FGFR1-AMPK-FOXO1 signaling
0:00Welcome to Base My Base, the paper cast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. Today, we're embarking on a deep dive into one of the most stubborn and frankly heartbreaking global health crises out there.
0:15Diabetic kidney disease or DKD. I mean, if you have diabetes or you know someone who does, you know the stakes are incredibly high. DKD is the number one reason people end up with end stage renal disease.
0:25It affects up to 40% of people with diabetes worldwide. And when we talk about kidney failure, it often comes down to the failure of just one incredibly specialized type of cell. Think of the kidneys filter, the glamerolis as the super fine mesh, and holding that mesh together, these are really unique, almost fragile cells called potocytes.
0:46They literally wrap around the capillaries, creating that perfect barrier that keeps vital proteins in your blood. And that's the devastating part. In diabetes, those potocytes are, you know, they're the 1st victims.
0:57the canary in the coal mine. When they start to die off. When they detach or just undergo apoptosis, that whole barrier just collapses. And that's when you start seeing protein leak into the urine, which we call albuminuria.
1:09And it signals this irreversible spiral toward total kidney failure. So current treatments. And we do have some good ones, like SGLT 2 inhibitors. They do a pretty good job of slowing this all down. But like you just said, slowing isn't stopping.
1:23They don't solve the core problem. Right. They don't answer that fundamental question. Why are the poticites dying in the 1st place? We really need a therapeutic that's, you know, intrinsic to the poticide itself.
1:35A fundamental protective mechanism that stops the cell from just giving up in that high sugar, high stress environment. Which brings us to the really fascinating question at the heart of today's deep dive.
1:45What if the body already has a potent natural guardian, a kind of built-in 1st aid kit that just sort of runs out or stops working as DKD gets worse? The surprising candidate we're looking at is fibroblast growth factor 4, or FGF 4.
2:00And this research suggests it might be the critical switch between kidney failure and survival. Okay, let's unpack this. Before we get into all the mechanisms. We wanna take a moment to celebrate the rigor of this work.
2:10Today, we celebrate the team based at the State Cree laboratory of macromolecular drugs and large scale preparation at Wenzoo Medical University, and their collaborators, who have really advanced our understanding here.
2:22So just to give you a bit more context on DKD. Beyond the cell death we talked about. The disease also involve these big structural changes, the filter itself gets enlarged, that's glamarial or hypertrophy, and the support structures get stiff and expand.
2:35It all just reduces the kidneys ability to do its job. And while all that's happening, our current treatments, you know, they have their limits. Things like ACE inhibitors or the newer SGLT 2 inhibitors are great for blood pressure or inflammation, but they're not a silver bullet.
2:50They're not. If the poticite is already drowning in oxidative stress, these drugs are more of a life raft than a rescue, they don't flip on the cell's own powerful survival circuits. So researchers started looking for those survival circuits.
3:03Exactly. We know that things like AMPK, which is a sort of metabolic master switch, are crucial for helping cells survive stress, and in diabetes, these protective factors get turned down. So that led the research community right to the FGF family, which are known to be involved in tissue repair.
3:20The question was, could a specific one FGF 4 be the key to saving the poticite? And to answer that, they had to be incredibly thorough. The methodology here is really impressive. This wasn't just a simple experiment in a Petri dish.
3:33Not at all. It is a multi-pronged approach. They started with clinical samples, real renal tissues from DKD patients. And this is really cool. They actually isolated living poticites directly from the urine of patients.
3:45So they had a living human system to test on. Precisely. Then they moved to animal models. And they didn't just use one type of diabetes model. They use mice that mimic type one diabetes, and also the DVDD mice, which are a classic model for type 2.
3:59That's a powerful way to make sure the findings are broadly relevant. And then Kim, the genetic engineering, which seems to be where the real magic happens. It really is. They generated mice with what's called a poticite specific knockout, or PKO.
4:12Using a very precise system, they could delete key genes, like FGF 4 or the genes it talks to, but only in the poticides. Okay, let's pause on that for a second. Why go to all that trouble? Why not just knock out the gene and the whole mouse?
4:25That's a critical question. It's all about proving causality. If you knock out FGF 4 everywhere and the kidney gets worse. You don't know why. Was it the loss in the potacite? or maybe in the liver. I see. By deleting it only in the poticite.
4:39You prove that the effect is intrinsic to that one cell type. It isolates the mechanism completely. It makes the data so much cleaner. So then they did a therapeutic intervention, giving the mice recommenant FGF4.
4:51Yes, and they measured the results with some very sensitive assays. They didn't just look at basic kidney markers. They used something called FITC sinister and clearance to get a really accurate measure of the glomerular filtration rate, the GFR.
5:06It tells you exactly how well the kidney is working. So let's get to the findings. What did they actually discover? Well the 1st step was just establishing a connection. And they found one. In human DKD patients.
5:18FGF 4 expression was way down and it was located right in the pot of sites. The less FGF 4 a patient had, the worse their kidney injury. Okay, so it's a clear marker of the disease. But that's still just a correlation.
5:30This is where those knockout mice come in right? This is where it gets really interesting. They took diabetic mice and deleted FGF 4 only in their pot of sites, and the results were dramatic. DKD progression just accelerated terrifyingly.
5:42How much worse did it get? Compared to diabetic mice that still had their natural FGF4, the knockout mice saw their GFR their filtration rate drop by an additional 32%. Wow, that's a huge drop It's a severe loss of function.
5:55And their albuminuria and kidney scarring just went through the roof. This proves FGF 4 isn't just a marker. It's absolutely necessary for the kidneys natural defense. So if losing it makes things worse, can adding it back make things better?
6:11That was the next logical step. They treated both their type one and type 2 diabetic mouse models with recombinant FGF 4, and the results were consistently positive. It significantly reduced kidney injury across the board.
6:25And this leads to what I think is the most critical finding, the part that really opens up new therapeutic avenues. Yes. So while the RFGF4 treatment did loader blood glucose in the type 2 model. It completely failed to reduce blood glucose in the type one diabetic mice.
6:41Yet the kidneys still got better. The kidney still got better. Even with dangerously high blood sugar, the kidney protection still happened. And that's huge, because it means the benefits are non glycemic dependent.
6:51So the drug is talking directly to the dying cell. It's bypassing the whole issue of systemic blood sugar control. Exactly. It's a direct localized protective effect. That distinction changes everything.
7:01But how does it work? What's the molecular signal for survival? So they track the cascade. RFGF4 binds to a receptor on the pot aside called FGFR1. Once that's activated, it triggers an internal pathway, switching on this crucial MPKFOXO1 axis.
7:18The AMPKFOXO1 access. That's a bit of a mouthful. Can you walk us through what those 2 things are actually doing inside the cell? Absolutely. Think of AMPK as the cell's main energy sensor. When the potocyte is under diabetic stress, AMPK is like the low fuel light on your car's dashboard, it immediately switches on the sales backup power.
7:36And FOXO1 is that backup power. FOXO1 is the response. It a transcription factor. When AMPK activates it. FOXO1 goes into the nucleus and acts like a fire chief, ordering the cell to ramp up production of its antioxidant defenses.
7:49It's the mechanism that cleans up all the damaging free radicals that are so common in the diabetic kidney. So that cascade FGFR one to AMPK to F focus 01 is the whole key. And they proved it by taking those pieces outright.
8:00Yes. This is where that precise genetic engineering paid off again. When they knocked out either FGFR1, amp, or FOXO1, The protection from the RFGF4 treatment was completely abolished. Which has stopped working.
8:14Completely. The cell death continued, the oxidative stress return. It proves that this pathway is absolutely essential for FGF force protective function. And to top it all off, they brought this back to humans.
8:26They did. They showed that RFGF4 could reverse damage and restore the healthy shape of primary human poticites, including cells taken directly from DKD patients. That's very strong evidence for its therapeutic potential.
8:38So if we connect this to the bigger picture. This research really elevates FGF4 from just some obscure factor to what, a molecular guardian for the potocite. That's a perfect way to put it. Its natural decline in DKD is a key part of the disease, and restoring it seems to target the root cause of the renal failure.
8:56And the fact that it's glucose independent is so vital, it suggests a whole new way to treat this, one that doesn't just rely on managing blood sugar. It's an anti-death anti-stress system that you can turn back on.
9:07Now, you hear growth factor, and you immediately think about potential risks, right? Specifically cancer or uncontrolled cell growth. Did they look into that? They did, and that's a critical point for translation.
9:20They checked for any signs of tumor promotion or increased cell proliferation after giving the RFGF4. And crucially, they found no evidence of any increase. It seems to be focused specifically on self survival and repair, not proliferation, which is a very promising safety profile to start with.
9:37That is very reassuring. So how does this new pathway fit in with the drugs we already use? That's another great question they explored. They found that Lisartan, which is a common 1st line blood pressure drug, actually increased the poticite's own production of FGF 4.
9:51Oh, interesting. So its protective effect might be partly due to this pathway. It seems like it. But the SGLT 2 inhibitor, in Bagel Flawson, didn't affect FGF 4 levels at all. And that's a really valuable finding.
10:02Why is that? It suggests that a combination therapy could be incredibly effective. You could use an SGLT 2 inhibitor for the metabolic benefits and an FGF 4-based therapy to directly protect the potacite.
10:13They'd be working on 2 different complementary pathways. So, to distill the central insight for you, the listener, and wrap up this deep dive. FGF 4 acts as a powerful signaling molecule. It uses the FGFR1 receptor to activate the AMPKFRXO1 pathway inside potocytes.
10:31This specific glucose independent cascade is essential for fighting oxidative stress and preventing cell death, which in turn promotes potocite survival, and can halt the progression of diabetic kidney disease.
10:41And that leaves us with a final thought-provoking prompt. Given the highly targeted glucose independent nature of this rescue mechanism. What does this mean for the future development of DKD treatments?
10:52Will combination therapies that restore FGF 4 signaling become the new standard of care. This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description.
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