Saturday, December 21, 2024
12/21/2024
Abstract Despite decades of treatment with ACE inhibitors and Angiotensin II receptor blockers, and the recent addition of SGLT2 inhibitors, chronic kidney disease (CKD) patients continue to progress towards end stage kidney disease. While studying mechanisms of proteinuria and kidney disease a decade ago, we identified and published circulating sialylated Angiopoietin-like-4 (ANGPTL4) and mutated versions of the human protein as a potential therapy to reduce proteinuria via interaction with glomerular integrins. Subsequent studies (preliminary data in this proposal) have now shown that transgene secreted rat ANGPTL4 and the mutated human ANGPTL4 protein 8520 reduce the progression of CKD in rat models of focal and segmental glomerulosclerosis (FSGS)and diabetic nephropathy (DN), respectively. Moreover, the preservation of inulin clearance glomerular filtration rate (GFR) in diabetic rats treated with 8520 was superior to control treated rats, and 8520 + ACE inhibitors superior to control treated rats or rats treated with ACE inhibitors alone. We further noted that 8520 treatment reduces kidney interstitial capillary apoptosis significantly, thereby also reducing interstitial fibrosis, potentially via interaction with integrins. In this proposal, we plan to extend our mechanistic studies on the beneficial interaction of 8520 with integrins in kidney interstitial capillaries, while also extending potential therapeutic studies in rat models of DN and FSGS, that include comparisons with ACE inhibitors and SGLT2 inhibitors, and additional vital sign monitoring using telemetry. Finally, we study potential therapeutic effects of 8520 in a large animal (minipig) model of CKD. In Aim 1, 8520 efficacy in improving CKD will be studied in ZSF1 diabetic rats and Buffalo Mna (FSGS) rats, including comparisons and combinations with ACE inhibitors, SGLT2 inhibitors and controls. In Aim 2, we will study whether the anti-apoptosis effects of 8520 on kidney interstitial capillaries are mediated via Integrin β1 or Integrin β5. Additional Mass Spectrometry studies on purified 8520 will be conducted to develop an assay to monitor plasma levels, and an ELISA to study potential immune response to mutations in 8520 will be developed. In Aim 3, the autologous phase of nephrotoxic nephritis will be studied in minipigs to determine the efficacy of 8520 in slowing the progression of CKD in a large animal model.
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